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Armstrong, Andrew John

Overview:

1. Predictors of sensitivity and clinical efficacy of therapies in advanced prostate cancer
2. Novel designs of clinical trials and pharmacodynamic/translational studies in prostate, kidney, bladder cancer
3. Pre-operative models for drug development of novel agents in human testing in prostate cancer
4. Novel therapies and drug development for prostate, renal, bladder, and testicular cancer
5. Design of rational combination therapies in men with metastatic hormone-refractory prostate cancer
6. PI3 kinase/mTOR inhibition in prostate cancer: mechanisms of sensitivity and resistance
7. Developing prognostic models for progression and survival in metastatic prostate cancer
8. Examining surrogate markers of mortality in metastatic prostate cancer
9. Clear cell and non-clear cell renal cell carcinoma: natural history, sensitivity to novel agents including mTOR and VEGF inhibition

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Associate Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Associate Professor in Surgery

Surgery, Urology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S.E. 1996

B.S.E. — Duke University

M.D. 2000

M.D. — University of Virginia School of Medicine

M.Sc. 2008

M.Sc. — Johns Hopkins University

Internship/Residency, General Internal Medicine

University of Pennsylvania School of Medicine

Fellowship, Division Of Oncology/Hematology

Johns Hopkins University School of Medicine

News:

Grants:

A Phase 2 Study of Nivolumab in combination with either Rucaparib, docetaxel, or enzalutamide in men with Castration-resistant metastaic prostate cancer (CheckMate 9KD: CHECKpoint pathway and nivoluMA

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
July 31, 2018
End Date
July 31, 2023

MK7123

Administered By
Duke Cancer Institute
AwardedBy
Merck Sharp & Dohme
Role
Principal Investigator
Start Date
June 18, 2018
End Date
June 17, 2023

NEPC Trial PD-1 Inhibition in Neuroendocrine-like Prostate Cancer (PD-1 Inhibition or Combination Checkpoint Immuntherapy of Neuroedocrine_Like Prostate Cancer

Administered By
Duke Cancer Institute
AwardedBy
Pfizer, Inc.
Role
Principal Investigator
Start Date
October 26, 2017
End Date
June 30, 2022

A Phase 1B, Open-Label Study of the Safety and Tolerability of Atezolizumab in Combination with Radium-223 Dichloride in Patients with Castrate-Resistant Prostate Cancer who have progressed followinIn

Administered By
Duke Cancer Institute
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
March 02, 2017
End Date
March 31, 2022

Targeting the p38/Snail/PD-L1 axis in hormone-therapy resistance and metastasis

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 01, 2018
End Date
October 31, 2021

PCRP Clinical Consortium: Duke University Clinical Research Site

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
March 01, 2007
End Date
September 29, 2021

Plasma Angiome and Serum Androgens as Predictors of Overall Survival in Metastatic Prostate Cancer

Administered By
Biostatistics & Bioinformatics
AwardedBy
Department of Defense
Role
Partnering PI
Start Date
September 01, 2018
End Date
August 31, 2021

Plasma Angiome and Serum Androgens as Predictors of Overall Survival in Metastatic Prostate Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 01, 2018
End Date
August 31, 2021

GS-5829 mono and combo enzalutamide

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2021

A Randomized Phase 2 Study of Sipuleucel-T with or without Radium-223

Administered By
Duke Cancer Institute
AwardedBy
Johns Hopkins University
Role
Principal Investigator
Start Date
February 03, 2017
End Date
February 14, 2021

Targeting Convergent Mechanisms of Therapy Resistance, Metastasis, and Immune Evasion with CBP inhibitors

Administered By
Medicine, Medical Oncology
AwardedBy
FORMA Therapeutics, Inc.
Role
Co Investigator
Start Date
October 03, 2018
End Date
October 02, 2020

A Phase III, Open Label, Randomized Study to Assess the Efficacy and Safety of Olaparib (Lynparza¿) Versus Enzalutamide or Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Canc

Administered By
Duke Cancer Institute
AwardedBy
AstraZeneca Pharmaceuticals, LP
Role
Principal Investigator
Start Date
February 13, 2018
End Date
February 29, 2020

CTC-Immune Checkpoints

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Principal Investigator
Start Date
January 28, 2016
End Date
January 27, 2020

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
AwardedBy
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
Start Date
January 01, 2017
End Date
December 31, 2019

A Phase 2 Trial of the Aurora Kinase A Inhibitor MLN8237 in Patients with Metastatic Castrate Resistant and Neuro

Administered By
Duke Cancer Institute
AwardedBy
Weill Medical College of Cornell University
Role
Principal Investigator
Start Date
November 01, 2013
End Date
October 31, 2019

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
AwardedBy
Prostate Cancer Foundation
Role
Principal Investigator
Start Date
August 01, 2014
End Date
August 01, 2019

STREAM - Salvage Therapeutic Radiation with Enzalutamide and ADT in Men with Recurrent Prostate Cancer

Administered By
Duke Cancer Institute
AwardedBy
Astellas Pharma Global Development, Inc
Role
Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2019

Testing the efficacy of AR degrading compounds in enzalutamide-resistant prostate cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Arvinas Inc.
Role
Investigator
Start Date
January 05, 2017
End Date
January 08, 2019

Pharmacodynamic Study of Radium-223 in Men with Bone Metastatic Castration-Resistant Prostate Cancer (CRPC)

Administered By
Duke Cancer Institute
AwardedBy
Bayer Corporation
Role
Principal Investigator
Start Date
June 01, 2014
End Date
December 31, 2018

AR variant regulation during EMT and disease progression

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2015
End Date
July 31, 2018

A Randomized, Open label, Muiticenter, Phase III, 2 Arm Study of Androgen Deprivation with Leuprilode +/- Docetaxel for

Administered By
Duke Cancer Institute
AwardedBy
Memorial Sloan Kettering Cancer Center
Role
Principal Investigator
Start Date
August 01, 2013
End Date
June 14, 2017

Prognostic Models of Clinical Outcomes In Men With Castration Resistant Prostate Cancer

Administered By
Biostatistics & Bioinformatics
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 06, 2011
End Date
May 31, 2016

Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
December 01, 2008
End Date
November 30, 2014
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Publications:

Updates in advanced prostate cancer 2018.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Updates in advanced prostate cancer 2018." Prostate Cancer and Prostatic Diseases (October 2, 2018).
PMID
30279577
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Publish Date
2018
DOI
10.1038/s41391-018-0100-7

Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas.

Cancer metastasis and therapy resistance are the major unsolved clinical challenges, and account for nearly all cancer-related deaths. Both metastasis and therapy resistance are fueled by epithelial plasticity, the reversible phenotypic transitions between epithelial and mesenchymal phenotypes, including epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). EMT and MET have been largely considered as binary processes, where cells detach from the primary tumor as individual units with many, if not all, traits of a mesenchymal cell (EMT) and then convert back to being epithelial (MET). However, recent studies have demonstrated that cells can metastasize in ways alternative to traditional EMT paradigm; for example, they can detach as clusters, and/or occupy one or more stable hybrid epithelial/mesenchymal (E/M) phenotypes that can be the end point of a transition. Such hybrid E/M cells can integrate various epithelial and mesenchymal traits and markers, facilitating collective cell migration. Furthermore, these hybrid E/M cells may possess higher tumor-initiation and metastatic potential as compared to cells on either end of the EMT spectrum. Here, we review in silico, in vitro, in vivo and clinical evidence for the existence of one or more hybrid E/M phenotype(s) in multiple carcinomas, and discuss their implications in tumor-initiation, tumor relapse, therapy resistance, and metastasis. Together, these studies drive the emerging notion that cells in a hybrid E/M phenotype may occupy 'metastatic sweet spot' in multiple subtypes of carcinomas, and pathways linked to this (these) hybrid E/M state(s) may be relevant as prognostic biomarkers as well as a promising therapeutic targets.

Authors
Jolly, MK; Somarelli, JA; Sheth, M; Biddle, A; Tripathi, SC; Armstrong, AJ; Hanash, SM; Bapat, SA; Rangarajan, A; Levine, H
MLA Citation
Jolly, MK, Somarelli, JA, Sheth, M, Biddle, A, Tripathi, SC, Armstrong, AJ, Hanash, SM, Bapat, SA, Rangarajan, A, and Levine, H. "Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas." Pharmacology & Therapeutics (September 28, 2018). (Review)
PMID
30268772
Source
epmc
Published In
Pharmacology & Therapeutics
Publish Date
2018
DOI
10.1016/j.pharmthera.2018.09.007

A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers.

Purpose: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth.Experimental Design: Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed.Results: Median PSA was 1.13 ng/mL (0.01-514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3-13). Exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption.Conclusions: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib. Clin Cancer Res; 1-9. ©2018 AACR.

Authors
Beltran, H; Oromendia, C; Danila, DC; Montgomery, B; Hoimes, C; Szmulewitz, RZ; Vaishampayan, U; Armstrong, AJ; Stein, M; Pinski, J; Mosquera, JM; Sailer, V; Bareja, R; Romanel, A; Gumpeni, N; Sboner, A; Dardenne, E; Puca, L; Prandi, D; Rubin, MA; Scher, HI; Rickman, DS; Demichelis, F; Nanus, DM; Ballman, KV; Tagawa, ST
MLA Citation
Beltran, H, Oromendia, C, Danila, DC, Montgomery, B, Hoimes, C, Szmulewitz, RZ, Vaishampayan, U, Armstrong, AJ, Stein, M, Pinski, J, Mosquera, JM, Sailer, V, Bareja, R, Romanel, A, Gumpeni, N, Sboner, A, Dardenne, E, Puca, L, Prandi, D, Rubin, MA, Scher, HI, Rickman, DS, Demichelis, F, Nanus, DM, Ballman, KV, and Tagawa, ST. "A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research (September 19, 2018).
PMID
30232224
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Publish Date
2018
DOI
10.1158/1078-0432.ccr-18-1912

Precision Medicine Approaches When Prostate Cancer Akts Up.

Ipatasertib combined with abiraterone in PTEN-null prostate cancer improved progression-free survival in a randomized phase II study of patients with metastatic castration-resistant prostate cancer (mCRPC), providing clinical evidence of reciprocal activation between the Akt and androgen receptor (AR) pathways. These data revive the rationale for targeting PTEN loss in prostate cancer. Clin Cancer Res; 1-3. ©2018 AACR. See related article by de Bono et al.

Authors
Zhang, T; George, DJ; Armstrong, AJ
MLA Citation
Zhang, T, George, DJ, and Armstrong, AJ. "Precision Medicine Approaches When Prostate Cancer Akts Up." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research (September 11, 2018).
PMID
30206162
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Publish Date
2018
DOI
10.1158/1078-0432.ccr-18-2491

Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide.Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2:1 into training (n=1159) and testing (n=550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set.Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups.Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design.ClinicalTrials.gov: NCT01212991.

Authors
Armstrong, AJ; Lin, P; Higano, CS; Sternberg, CN; Sonpavde, G; Tombal, B; Templeton, AJ; Fizazi, K; Phung, D; Wong, EK; Krivoshik, A; Beer, TM
MLA Citation
Armstrong, AJ, Lin, P, Higano, CS, Sternberg, CN, Sonpavde, G, Tombal, B, Templeton, AJ, Fizazi, K, Phung, D, Wong, EK, Krivoshik, A, and Beer, TM. "Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer." Annals of Oncology : Official Journal of the European Society for Medical Oncology (September 10, 2018).
PMID
30202945
Source
epmc
Published In
Annals of Oncology
Publish Date
2018
DOI
10.1093/annonc/mdy406

The evolving landscape of metastatic hormone-sensitive prostate cancer: a critical review of the evidence for adding docetaxel or abiraterone to androgen deprivation.

Until 2015, androgen deprivation therapy (ADT) alone was the standard-of-care for metastatic hormone-sensitive prostate cancer (mHSPC). In 2015, the CHAARTED and STAMPEDE-Docetaxel studies demonstrated marked survival benefit with the addition of docetaxel to ADT in the mHSPC setting, leading to a change in the standard-of-care for mHSPC. The recent LATITUDE and STAMPEDE-Abiraterone trials showed similar substantial improvement in survival with the addition of abiraterone plus prednisone to ADT in this space.We conducted a review of the randomized phase III studies that have investigated either the addition of docetaxel or abiraterone to ADT in patients with mHSPC.We describe the study designs, key eligibility criteria, and key results for the CHAARTED, STAMPEDE-Docetaxel, GETUG-AFU 15, LATITUDE, and STAMPEDE-Abiraterone clinical trials. We compare the data for abiraterone/prednisone plus ADT in mHSPC with the evidence for docetaxel plus ADT in these patients. Finally, we discuss several factors that should be considered when choosing between docetaxel/ADT or abiraterone/prednisone/ADT in mHSPC.The management of mHSPC is evolving. Abiraterone plus prednisone in addition to ADT has emerged as an alternative standard-of-care to docetaxel plus ADT, and ongoing trials should clarify whether combination vs. sequential approaches with AR-targeting agents and taxane chemotherapy are preferred for initial management in the hormone-sensitive setting.

Authors
McNamara, M; Sweeney, C; Antonarakis, ES; Armstrong, AJ
MLA Citation
McNamara, M, Sweeney, C, Antonarakis, ES, and Armstrong, AJ. "The evolving landscape of metastatic hormone-sensitive prostate cancer: a critical review of the evidence for adding docetaxel or abiraterone to androgen deprivation." Prostate Cancer and Prostatic Diseases 21.3 (September 2018): 306-318. (Review)
PMID
29263421
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
21
Issue
3
Publish Date
2018
Start Page
306
End Page
318
DOI
10.1038/s41391-017-0014-9

Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?

Intermediate endpoints are needed in early phase studies of men with metastatic castration-resistant prostate cancer (mCRPC) that can reliably predict success in phase 3 trials. Among men with measurable disease, objective response may provide information as to whether a treatment is likely to be successful.We conducted a systematic review of systemic agents that have proceeded to phase 3 trials in men with mCRPC and examined the relationship between improvements in measurable disease response in phase 2 trials and successful phase 3 trials leading to regulatory approval. Only trials that included men with radiographically measurable disease were included.We examined 31 eligible mCRPC phase 3 trials between 1992 and 2017 and 29 of the preceding phase 2 trials for RECIST responses. Measurable tumor responses in phase 2 trials were higher for successful therapies in phase 3 trials in chemotherapy-naive men with mCRPC, but were less correlated with success in trials investigating docetaxel combination regimens or the post chemotherapy mCRPC setting. Many failed agents did not produce higher than expected response rates over control arms; however, several agents such as anti-angiogenic therapies or orteronel produced higher than expected responses without survival benefit.Objective responses in men with mCRPC may be associated with prolonged survival, but this association is mechanism dependent and inconsistent across trials or disease states. These data support considering RECIST response as a supportive but not sole endpoint in phase 2 trials to support launching phase 3 trials.

Authors
Brown, LC; Sonpavde, G; Armstrong, AJ
MLA Citation
Brown, LC, Sonpavde, G, and Armstrong, AJ. "Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?." Prostate Cancer and Prostatic Diseases 21.3 (September 2018): 419-430.
PMID
29858595
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
21
Issue
3
Publish Date
2018
Start Page
419
End Page
430
DOI
10.1038/s41391-018-0049-6

Circulating Tumor Cell Phenotyping via High-Throughput Acoustic Separation.

The study of circulating tumor cells (CTCs) offers pathways to develop new diagnostic and prognostic biomarkers that benefit cancer treatments. In order to fully exploit and interpret the information provided by CTCs, the development of a platform is reported that integrates acoustics and microfluidics to isolate rare CTCs from peripheral blood in high throughput while preserving their structural, biological, and functional integrity. Cancer cells are first isolated from leukocytes with a throughput of 7.5 mL h-1 , achieving a recovery rate of at least 86% while maintaining the cells' ability to proliferate. High-throughput acoustic separation enables statistical analysis of isolated CTCs from prostate cancer patients to be performed to determine their size distribution and phenotypic heterogeneity for a range of biomarkers, including the visualization of CTCs with a loss of expression for the prostate specific membrane antigen. The method also enables the isolation of even rarer, but clinically important, CTC clusters.

Authors
Wu, M; Huang, P-H; Zhang, R; Mao, Z; Chen, C; Kemeny, G; Li, P; Lee, AV; Gyanchandani, R; Armstrong, AJ; Dao, M; Suresh, S; Huang, TJ
MLA Citation
Wu, M, Huang, P-H, Zhang, R, Mao, Z, Chen, C, Kemeny, G, Li, P, Lee, AV, Gyanchandani, R, Armstrong, AJ, Dao, M, Suresh, S, and Huang, TJ. "Circulating Tumor Cell Phenotyping via High-Throughput Acoustic Separation." Small (Weinheim an Der Bergstrasse, Germany) 14.32 (August 2018): e1801131-null.
PMID
29968402
Source
epmc
Published In
Small (Weinheim an Der Bergstrasse, Germany)
Volume
14
Issue
32
Publish Date
2018
Start Page
e1801131
DOI
10.1002/smll.201801131

Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m (99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data.To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).This investigation was a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017.The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain.Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95% CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95% CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95% CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95% CI, 1.14-1.30; P < .001).To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.ClinicalTrials.gov Identifier: NCT01234311.

Authors
Armstrong, AJ; Anand, A; Edenbrandt, L; Bondesson, E; Bjartell, A; Widmark, A; Sternberg, CN; Pili, R; Tuvesson, H; Nordle, Ö; Carducci, MA; Morris, MJ
MLA Citation
Armstrong, AJ, Anand, A, Edenbrandt, L, Bondesson, E, Bjartell, A, Widmark, A, Sternberg, CN, Pili, R, Tuvesson, H, Nordle, Ö, Carducci, MA, and Morris, MJ. "Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial." Jama Oncology 4.7 (July 2018): 944-951.
PMID
29799999
Source
epmc
Published In
Jama Oncology
Volume
4
Issue
7
Publish Date
2018
Start Page
944
End Page
951
DOI
10.1001/jamaoncol.2018.1093

Is Ki67 prognostic for aggressive prostate cancer? A multicenter real-world study.

AIM:To test if Ki67 expression is prognostic for biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS:Ki67 immunohistochemistry was performed on tissue microarrays constructed from specimens obtained from 464 men undergoing RP at the Durham and West LA Veterans Affairs Hospitals. Hazard ratios (HR) for Ki67 expression and time to BCR were estimated using Cox regression. RESULTS:Ki67 was associated with more recent surgery year (p < 0.001), positive margins (p = 0.001) and extracapsular extension (p < 0.001). In center-stratified analyses, the adjusted HR for Ki67 expression and BCR approached statistical significance for west LA (HR: 1.54; p = 0.06), but not Durham (HR: 1.10; p = 0.74). CONCLUSION:This multi-institutional 'real-world' study provides limited evidence for the prognostic role of Ki67 in predicting outcome after RP.

Authors
Fantony, JJ; Howard, LE; Csizmadi, I; Armstrong, AJ; Lark, AL; Galet, C; Aronson, WJ; Freedland, SJ
MLA Citation
Fantony, JJ, Howard, LE, Csizmadi, I, Armstrong, AJ, Lark, AL, Galet, C, Aronson, WJ, and Freedland, SJ. "Is Ki67 prognostic for aggressive prostate cancer? A multicenter real-world study." Biomarkers in Medicine 12.7 (July 2018): 727-736.
PMID
29902938
Source
epmc
Published In
Biomarkers in Medicine
Volume
12
Issue
7
Publish Date
2018
Start Page
727
End Page
736
DOI
10.2217/bmm-2017-0322

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients.To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS.PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016.Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula.In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ.Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.clinicaltrials.gov Identifier: NCT01212991.

Authors
Rathkopf, DE; Beer, TM; Loriot, Y; Higano, CS; Armstrong, AJ; Sternberg, CN; de Bono, JS; Tombal, B; Parli, T; Bhattacharya, S; Phung, D; Krivoshik, A; Scher, HI; Morris, MJ
MLA Citation
Rathkopf, DE, Beer, TM, Loriot, Y, Higano, CS, Armstrong, AJ, Sternberg, CN, de Bono, JS, Tombal, B, Parli, T, Bhattacharya, S, Phung, D, Krivoshik, A, Scher, HI, and Morris, MJ. "Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial." Jama Oncology 4.5 (May 2018): 694-701.
PMID
29522174
Source
epmc
Published In
Jama Oncology
Volume
4
Issue
5
Publish Date
2018
Start Page
694
End Page
701
DOI
10.1001/jamaoncol.2017.5808

Platinum sensitivity in metastatic prostate cancer: does histology matter?

BACKGROUND:Platinum-based chemotherapy is effective in men with neuroendocrine prostate cancer (NEPC), but it is unclear whether histology (adenocarcinoma vs. non-adenocarcinoma NEPC variants) is predictive of platinum sensitivity. Given that NEPC exists as a spectrum, there may be men with adenocarcinoma who might benefit from platinum chemotherapy, particularly those men with DNA repair defects. METHODS:This was a retrospective study of all of the men seen at Duke University since 2005 who had metastatic castration-resistant prostate cancer (mCRPC) and were treated with a platinum agent. Data surrounding clinical features, histology, imaging, safety, and neuroendocrine transformation were collected. Scans were re-reviewed using RECIST v1.1 criteria to estimate responses as well as calculate radiographic progression-free survival (rPFS). RESULTS:A database search identified 73 men with mCRPC treated with cisplatin, carboplatin, or oxaliplatin. There were three men with primary NEPC and small cell prostate cancer, and 14 with a NEPC transformation. In the first-line setting, 10 (63%) men with NEPC had a partial response (PR) compared with 14 (29%) of the men with adenocarcinoma (p = 0.017), with a median rPFS of 5.1 mo (3.1-7.8) and 4.3 mo (3.0-5.2 mo), respectively. The median overall survival was 8.5 mo (6.4-20.1 mo) for men with NEPC compared to 10.0 mo (8.0-14.4) in men with adenocarcinoma. Prostate-specific antigen (PSA) declines meeting >30%, >50%, and >90% criteria from baseline were observed in 64/57/29% of NEPC patients (n = 14) treated with platinum chemotherapy vs. 48/30/14% of men with prostate adenocarcinoma (n = 50), respectively. CONCLUSIONS:This study suggests that NEPC histology enriches for platinum sensitivity, but that an important minority group (20-30%) of men with adenocarcinoma have a clinical benefit with platinum-based chemotherapy. Molecular predictors, such as germline or somatic mutations in DNA repair enzymes, should be evaluated for platinum responsiveness.

Authors
Humeniuk, MS; Gupta, RT; Healy, P; McNamara, M; Ramalingam, S; Harrison, M; George, D; Zhang, T; Wu, Y; Armstrong, AJ
MLA Citation
Humeniuk, MS, Gupta, RT, Healy, P, McNamara, M, Ramalingam, S, Harrison, M, George, D, Zhang, T, Wu, Y, and Armstrong, AJ. "Platinum sensitivity in metastatic prostate cancer: does histology matter?." Prostate Cancer and Prostatic Diseases 21.1 (April 2018): 92-99.
PMID
29230006
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
21
Issue
1
Publish Date
2018
Start Page
92
End Page
99
DOI
10.1038/s41391-017-0017-6

Clinical utility of non-EpCAM based circulating tumor cell assays.

Methods enabling the isolation, detection, and characterization of circulating tumor cells (CTCs) in blood have clear potential to facilitate precision medicine approaches in patients with cancer, not only for prognostic purposes but also for prediction of the benefits of specific therapies in oncology. However, current CTC assays, which capture CTCs based on expression of epithelial cell adhesion molecule (EpCAM), fail to capture cells from de-differentiated tumors and carcinomas undergoing loss of the epithelial phenotype during the invasion/metastatic process. To address this limitation, many groups are developing non-EpCAM based CTC assays that incorporate nanotechnology to improve test sensitivity for rare but important cells that may otherwise go undetected, and therefore may improve upon clinical utility. In this review, we outline emerging non-EpCAM based CTC assays utilizing nanotechnology approaches for CTC capture or characterization, including dendrimers, magnetic nanoparticles, gold nanoparticles, negative selection chip or software-based on-slide methods, and nano-scale substrates. In addition, we address challenges that remain for the clinical translation of these platforms.

Authors
Austin, RG; Huang, TJ; Wu, M; Armstrong, AJ; Zhang, T
MLA Citation
Austin, RG, Huang, TJ, Wu, M, Armstrong, AJ, and Zhang, T. "Clinical utility of non-EpCAM based circulating tumor cell assays." Advanced Drug Delivery Reviews 125 (February 2018): 132-142. (Review)
PMID
29366804
Source
epmc
Published In
Advanced Drug Delivery Reviews
Volume
125
Publish Date
2018
Start Page
132
End Page
142
DOI
10.1016/j.addr.2018.01.013

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond.

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

Authors
Zhu, J; Armstrong, AJ; Friedlander, TW; Kim, W; Pal, SK; George, DJ; Zhang, T
MLA Citation
Zhu, J, Armstrong, AJ, Friedlander, TW, Kim, W, Pal, SK, George, DJ, and Zhang, T. "Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond." Journal for Immunotherapy of Cancer 6.1 (January 25, 2018): 4-null. (Review)
Website
http://hdl.handle.net/10161/16029
PMID
29368638
Source
epmc
Published In
Journal for Immunotherapy of Cancer
Volume
6
Issue
1
Publish Date
2018
Start Page
4
DOI
10.1186/s40425-018-0314-1

Naming disease states for clinical utility in prostate cancer: a rose by any other name might not smell as sweet.

Authors
Armstrong, AJ; Antonarakis, ES; Taplin, M-E; Kelly, WK; Beltran, H; Fizazi, K; Dahut, WL; Shore, N; Slovin, S; George, D; Carducci, MA; Corn, P; Danila, D; Dreicer, R; Heath, E; Rathkopf, D; Liu, G; Nanus, D; Stein, M; Smith, MR; Sternberg, C; Wilding, G; Nelson, PS; Halabi, S; Kantoff, P; Clarke, NW; Evans, CP; Heidenreich, A; Mottet, N; Gleave, M; Morris, MJ; Scher, HI
MLA Citation
Armstrong, AJ, Antonarakis, ES, Taplin, M-E, Kelly, WK, Beltran, H, Fizazi, K, Dahut, WL, Shore, N, Slovin, S, George, D, Carducci, MA, Corn, P, Danila, D, Dreicer, R, Heath, E, Rathkopf, D, Liu, G, Nanus, D, Stein, M, Smith, MR, Sternberg, C, Wilding, G, Nelson, PS, Halabi, S, Kantoff, P, Clarke, NW, Evans, CP, Heidenreich, A, Mottet, N, Gleave, M, Morris, MJ, and Scher, HI. "Naming disease states for clinical utility in prostate cancer: a rose by any other name might not smell as sweet." Annals of Oncology : Official Journal of the European Society for Medical Oncology 29.1 (January 2018): 23-25.
PMID
29088323
Source
epmc
Published In
Annals of Oncology
Volume
29
Issue
1
Publish Date
2018
Start Page
23
End Page
25
DOI
10.1093/annonc/mdx648

Acute Myeloid Leukemia After Olaparib Treatment in Metastatic Castration-Resistant Prostate Cancer.

Authors
Zhu, J; Tucker, M; Wang, E; Grossman, JS; Armstrong, AJ; George, DJ; Zhang, T
MLA Citation
Zhu, J, Tucker, M, Wang, E, Grossman, JS, Armstrong, AJ, George, DJ, and Zhang, T. "Acute Myeloid Leukemia After Olaparib Treatment in Metastatic Castration-Resistant Prostate Cancer." Clinical Genitourinary Cancer 15.6 (December 2017): e1137-e1141.
Website
https://hdl.handle.net/10161/17206
PMID
28780018
Source
epmc
Published In
Clinical Genitourinary Cancer
Volume
15
Issue
6
Publish Date
2017
Start Page
e1137
End Page
e1141
DOI
10.1016/j.clgc.2017.07.005

Clinical Outcomes of Chemotherapy Naïve Men with Metastatic Castration Resistant Prostate Cancer and Low Baseline Prostate Specific Antigen Treated with Enzalutamide vs Placebo.

Metastatic castration resistant prostate cancer with low baseline prostate specific antigen represents an early stage in the natural history of castration resistant prostate cancer progression (low volume disease), low prostate specific antigen producing disease or disease that is less dependent on androgen receptor biology (high volume disease). We analyzed outcomes in men with low prostate specific antigen and a high disease burden who received the oral androgen receptor inhibitor enzalutamide in the PREVAIL (Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients with Progressive Metastatic Prostate Cancer) study.In this exploratory analysis low baseline prostate specific antigen was defined as less than 10 ng/ml. Post hoc analyses included radiographic progression-free and overall survival in the once daily enzalutamide and placebo arms. Patients were stratified post hoc by high volume disease, defined as more than 4 bone metastases and/or visceral disease, and low volume disease, defined as 4 or fewer bone metastases with no visceral disease.Of 1,717 patients enrolled in PREVAIL 242 (14.1%) had low baseline prostate specific antigen, including 110 with high volume disease. Enzalutamide decreased the risk of radiographic progression relative to placebo in patients with low baseline prostate specific antigen (HR 0.20, 95% CI 0.10-0.42). This decrease was irrespective of tumor burden (high volume disease HR 0.17, 95% CI 0.06-0.51 and low volume disease HR 0.25, 95% CI 0.09-0.70). Median overall survival was not reached in patients with low baseline prostate specific antigen in either treatment arm.Chemotherapy naïve men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen irrespective of disease burden may benefit from enzalutamide. This indicates that targeting the androgen receptor signaling pathway is a therapeutic option in similar patients.

Authors
Taplin, M-E; Armstrong, AJ; Lin, P; Krivoshik, A; Phung, D; Parli, T; Tombal, B; Beer, TM
MLA Citation
Taplin, M-E, Armstrong, AJ, Lin, P, Krivoshik, A, Phung, D, Parli, T, Tombal, B, and Beer, TM. "Clinical Outcomes of Chemotherapy Naïve Men with Metastatic Castration Resistant Prostate Cancer and Low Baseline Prostate Specific Antigen Treated with Enzalutamide vs Placebo." The Journal of urology 198.6 (December 2017): 1324-1332.
PMID
28736322
Source
epmc
Published In
The Journal of Urology
Volume
198
Issue
6
Publish Date
2017
Start Page
1324
End Page
1332
DOI
10.1016/j.juro.2017.07.071

The who, what, and how of cabazitaxel treatment in metastatic castration-resistant prostate cancer

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "The who, what, and how of cabazitaxel treatment in metastatic castration-resistant prostate cancer." Journal of Clinical Oncology 35.28 (October 1, 2017): 3175-3177.
Source
scopus
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
28
Publish Date
2017
Start Page
3175
End Page
3177
DOI
10.1200/JCO.2017.74.7931

The Who, What, and How of Cabazitaxel Treatment in Metastatic Castration-Resistant Prostate Cancer.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "The Who, What, and How of Cabazitaxel Treatment in Metastatic Castration-Resistant Prostate Cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.28 (October 2017): 3175-3177.
PMID
28809609
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
28
Publish Date
2017
Start Page
3175
End Page
3177
DOI
10.1200/jco.2017.74.7931

RECISTing the Temptation to Prematurely Stop Nivolumab.

Authors
Humeniuk, MS; Armstrong, AJ
MLA Citation
Humeniuk, MS, and Armstrong, AJ. "RECISTing the Temptation to Prematurely Stop Nivolumab." European Urology 72.3 (September 2017): 377-378.
PMID
28454661
Source
epmc
Published In
European Urology
Volume
72
Issue
3
Publish Date
2017
Start Page
377
End Page
378
DOI
10.1016/j.eururo.2017.04.021

Exploiting DNA damage without repair: The activity of platinum chemotherapy in BRCA-mutated prostate cancers.

Authors
Humeniuk, MS; Zhang, T; Armstrong, AJ
MLA Citation
Humeniuk, MS, Zhang, T, and Armstrong, AJ. "Exploiting DNA damage without repair: The activity of platinum chemotherapy in BRCA-mutated prostate cancers." Cancer 123.18 (September 2017): 3441-3444.
PMID
28608923
Source
epmc
Published In
Cancer
Volume
123
Issue
18
Publish Date
2017
Start Page
3441
End Page
3444
DOI
10.1002/cncr.30806

Prognostic associations of prostate-specific antigen (PSA) decline with survival, radiographic response and progression in chemotherapy-naiive men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide

Authors
Armstrong, AJ; Lin, P; Higano, CS; Iversen, P; Sternberg, CN; Tombal, B; Phung, D; Parli, T; Krivoshik, A; Beer, TM
MLA Citation
Armstrong, AJ, Lin, P, Higano, CS, Iversen, P, Sternberg, CN, Tombal, B, Phung, D, Parli, T, Krivoshik, A, and Beer, TM. "Prognostic associations of prostate-specific antigen (PSA) decline with survival, radiographic response and progression in chemotherapy-naiive men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide." September 2017.
Source
wos-lite
Published In
Annals of Oncology
Volume
28
Publish Date
2017

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer.

Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor.This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months.Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5-23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I-II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders.Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.

Authors
Armstrong, AJ; Halabi, S; Healy, P; Alumkal, JJ; Winters, C; Kephart, J; Bitting, RL; Hobbs, C; Soleau, CF; Beer, TM; Slottke, R; Mundy, K; Yu, EY; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Alumkal, JJ, Winters, C, Kephart, J, Bitting, RL, Hobbs, C, Soleau, CF, Beer, TM, Slottke, R, Mundy, K, Yu, EY, and George, DJ. "Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer." August 2017.
PMID
28502694
Source
epmc
Published In
European Journal of Cancer
Volume
81
Publish Date
2017
Start Page
228
End Page
236
DOI
10.1016/j.ejca.2017.02.030

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

Authors
Armstrong, AJ; Halabi, S; Healy, P; Alumkal, JJ; Winters, C; Kephart, J; Bitting, RL; Hobbs, C; Soleau, CF; Beer, TM; Slottke, R; Mundy, K; Yu, EY; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Alumkal, JJ, Winters, C, Kephart, J, Bitting, RL, Hobbs, C, Soleau, CF, Beer, TM, Slottke, R, Mundy, K, Yu, EY, and George, DJ. "Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer." EUROPEAN JOURNAL OF CANCER 81 (August 2017): 228-236.
Source
wos-lite
Published In
European Journal of Cancer
Volume
81
Publish Date
2017
Start Page
228
End Page
236
DOI
10.1016/j.ejca.2017.02.030

Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC).This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase.This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively.The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy.The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate the total cost of care in mCPRC.

Authors
Armstrong, A; Bui, C; Fitch, K; Sawhney, TG; Brown, B; Flanders, S; Balk, M; Deangelis, J; Chambers, J
MLA Citation
Armstrong, A, Bui, C, Fitch, K, Sawhney, TG, Brown, B, Flanders, S, Balk, M, Deangelis, J, and Chambers, J. "Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations." June 2017.
PMID
28318331
Source
epmc
Published In
Current Medical Research and Opinion
Volume
33
Issue
6
Publish Date
2017
Start Page
1133
End Page
1139
DOI
10.1080/03007995.2017.1308919

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested.Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups.Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar.Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Authors
Bryce, AH; Alumkal, JJ; Armstrong, A; Higano, CS; Iversen, P; Sternberg, CN; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, TM
MLA Citation
Bryce, AH, Alumkal, JJ, Armstrong, A, Higano, CS, Iversen, P, Sternberg, CN, Rathkopf, D, Loriot, Y, de Bono, J, Tombal, B, Abhyankar, S, Lin, P, Krivoshik, A, Phung, D, and Beer, TM. "Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL." Prostate cancer and prostatic diseases 20.2 (June 2017): 221-227.
PMID
28117385
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
20
Issue
2
Publish Date
2017
Start Page
221
End Page
227
DOI
10.1038/pcan.2016.71

Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer.

PURPOSE: Evidence suggests differences in androgen receptor AR signaling between black (B) and white (W) patients with prostate cancer, but pivotal trials of abiraterone acetate (AA) for patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled few black patients, a population with a higher mortality from prostate cancer. Our primary objective was to determine differences in response to AA between B and W patients. METHODS: We performed a retrospective case-control study of B vs. W patients treated with AA between May 1, 2008 and June 16, 2015 at Duke University Medical Center. Patients were identified (W control patients were matched 2:1 to B patients stratified based on previous docetaxel exposure) through pharmacy records and were eligible if treated with AA for metastatic castration-resistant prostate cancer. Patients with previous enzalutamide use were excluded. The primary objective was to compare the rate of≥90% prostate-specific antigen (PSA) decline from baseline between B vs. W patients. Secondary outcomes included comparing time on therapy, time to PSA progression, and overall survival among groups. RESULTS: Baseline characteristics among patients (n = 45 B, n = 90 W) were identified; these included Karnofsky performance status, PSA, Gleason score, alkaline phosphatase, albumin, hemoglobin, lactate dehydrogenase, opiate use for pain, and metastatic sites. Baseline characteristics among groups were similar except for median hemoglobin (B = 11.4g/dl, W = 12.3g/dl). The proportion of B patients achieving a≥90% PSA level decline was 37.8% vs. 28.9% for W patients (P = 0.296). Statistically significant differences were found in the proportion of patients achieving a≥50% PSA level decline (B = 68.9%, W = 48.9% [P = 0.028]) and≥30% PSA level decline (B = 77.8%, W = 54.4% [P = 0.008]). Rates of primary abiraterone-refractory disease (PSA increase as best response) trended higher in W (31.1%) than in B (15.6%) patients (P = 0.052). Median treatment duration (B = 9.4 mo, W = 8.3 mo) did not differ (Wilcoxon P = 0.444). Median overall survival (B = 27.3 mo [95% CI: 13.9, not estimable], W = 24.8 mo [95% CI: 19, 31.6] [P = 0.669]) and median time to PSA progression (B = 11.0 mo [95% CI: 4.3, 18.0], W = 9.4 mo [95% CI: 6.2, 13.0] [P = 0.917]) did not differ. CONCLUSIONS: Black patients may have a higher PSA response to AA than white patients. An ongoing prospective clinical study (NCT01940276) is evaluating outcomes between black and white patients treated with AA.

Authors
Ramalingam, S; Humeniuk, MS; Hu, R; Rasmussen, J; Healy, P; Wu, Y; Harrison, MR; Armstrong, AJ; George, DJ; Zhang, T
MLA Citation
Ramalingam, S, Humeniuk, MS, Hu, R, Rasmussen, J, Healy, P, Wu, Y, Harrison, MR, Armstrong, AJ, George, DJ, and Zhang, T. "Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer." Urol Oncol 35.6 (June 2017): 418-424.
PMID
28126272
Source
pubmed
Published In
Urol Oncol
Volume
35
Issue
6
Publish Date
2017
Start Page
418
End Page
424
DOI
10.1016/j.urolonc.2016.12.016

Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting.Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment. Kaplan-Meier estimates evaluated the association of defined PSA changes from baseline with OS, progression-free survival (PFS), radiographic PFS (rPFS), and pain response. Each PSA decline category was assessed for OS surrogacy using Prentice criteria, proportion of treatment effect explained (PTE), and proportion of variation explained.Men treated with enzalutamide had improved OS (hazard ratio, 0.63; P < .001) and higher rates of PSA decline (odds ratio, >19.0; P < .001) versus placebo. PSA declines of any, ≥30%, ≥50%, and ≥90% with enzalutamide were strongly associated with greater OS, PSA PFS, rPFS (P < .001), and pain response (P < .026) versus PSA increase/no decline. Any, ≥30%, and ≥50% declines in PSA resulted in the PTE range of 1.07-1.29, where treatment was no longer significant after adjustment for decline measures (P > .20).PSA declines of any, ≥30%, and ≥50% following enzalutamide were associated with greater clinical and pain response and improvements in PFS and OS. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development. However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer 2017;123:2303-2311. © 2017 American Cancer Society.

Authors
Armstrong, AJ; Saad, F; Phung, D; Dmuchowski, C; Shore, ND; Fizazi, K; Hirmand, M; Forer, D; Scher, HI; Bono, JD
MLA Citation
Armstrong, AJ, Saad, F, Phung, D, Dmuchowski, C, Shore, ND, Fizazi, K, Hirmand, M, Forer, D, Scher, HI, and Bono, JD. "Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel." Cancer 123.12 (June 2017): 2303-2311.
PMID
28171710
Source
epmc
Published In
Cancer
Volume
123
Issue
12
Publish Date
2017
Start Page
2303
End Page
2311
DOI
10.1002/cncr.30587

Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells.

Phenotypic plasticity refers to a phenomenon in which cells transiently gain traits of another lineage. During carcinoma progression, phenotypic plasticity drives invasion, dissemination and metastasis. Indeed, while most of the studies of phenotypic plasticity have been in the context of epithelial-derived carcinomas, it turns out sarcomas, which are mesenchymal in origin, also exhibit phenotypic plasticity, with a subset of sarcomas undergoing a phenomenon that resembles a mesenchymal-epithelial transition (MET). Here, we developed a method comprising the miR-200 family and grainyhead-like 2 (GRHL2) to mimic this MET-like phenomenon observed in sarcoma patient samples.We sequentially express GRHL2 and the miR-200 family using cell transduction and transfection, respectively, to better understand the molecular underpinnings of these phenotypic transitions in sarcoma cells. Sarcoma cells expressing miR-200s and GRHL2 demonstrated enhanced epithelial characteristics in cell morphology and alteration of epithelial and mesenchymal biomarkers. Future studies using these methods can be used to better understand the phenotypic consequences of MET-like processes on sarcoma cells, such as migration, invasion, metastatic propensity, and therapy resistance.

Authors
Ware, KE; Gilja, S; Xu, S; Shetler, S; Jolly, MK; Wang, X; Bartholf Dewitt, S; Hish, AJ; Jordan, S; Eward, W; Levine, H; Armstrong, AJ; Somarelli, JA
MLA Citation
Ware, KE, Gilja, S, Xu, S, Shetler, S, Jolly, MK, Wang, X, Bartholf Dewitt, S, Hish, AJ, Jordan, S, Eward, W, Levine, H, Armstrong, AJ, and Somarelli, JA. "Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells." Journal of visualized experiments : JoVE 122 (April 7, 2017).
PMID
28448023
Source
epmc
Published In
Journal of Visualized Experiments : Jove
Issue
122
Publish Date
2017
DOI
10.3791/55520

Drug development in prostate cancer: time to embrace RECIST?

Authors
Sonpavde, G; Armstrong, AJ
MLA Citation
Sonpavde, G, and Armstrong, AJ. "Drug development in prostate cancer: time to embrace RECIST?." The Lancet. Oncology 18.4 (April 2017): 419-421.
PMID
28283283
Source
epmc
Published In
The Lancet. Oncology
Volume
18
Issue
4
Publish Date
2017
Start Page
419
End Page
421
DOI
10.1016/s1470-2045(17)30149-3

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial

Authors
Armstrong, AJ; Humeniuk, MS; Healy, P; Szmulewitz, R; Winters, C; Kephart, J; Harrison, MR; Martinez, E; Mundy, K; Halabi, S; George, D
MLA Citation
Armstrong, AJ, Humeniuk, MS, Healy, P, Szmulewitz, R, Winters, C, Kephart, J, Harrison, MR, Martinez, E, Mundy, K, Halabi, S, and George, D. "Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial." PROSTATE 77.4 (March 1, 2017): 385-395.
Source
wos-lite
Published In
Prostate
Volume
77
Issue
4
Publish Date
2017
Start Page
385
End Page
395
DOI
10.1002/pros.23277

Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer.

Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach.Experimental Design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential aCGH analyses of CTCs in the context of enzalutamide therapy.Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2 Analysis of aCGH in a sample with sequential enzalutamide-resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone.Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development. Clin Cancer Res; 23(5); 1346-57. ©2016 AACR.

Authors
Gupta, S; Li, J; Kemeny, G; Bitting, RL; Beaver, J; Somarelli, JA; Ware, KE; Gregory, S; Armstrong, AJ
MLA Citation
Gupta, S, Li, J, Kemeny, G, Bitting, RL, Beaver, J, Somarelli, JA, Ware, KE, Gregory, S, and Armstrong, AJ. "Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 23.5 (March 2017): 1346-1357.
PMID
27601596
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
23
Issue
5
Publish Date
2017
Start Page
1346
End Page
1357
DOI
10.1158/1078-0432.ccr-16-1211

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial.

BACKGROUND: Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC. METHODS: Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity. RESULTS: We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed. CONCLUSIONS: We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.

Authors
Armstrong, AJ; Humeniuk, MS; Healy, P; Szmulewitz, R; Winters, C; Kephart, J; Harrison, MR; Martinez, E; Mundy, K; Halabi, S; George, D
MLA Citation
Armstrong, AJ, Humeniuk, MS, Healy, P, Szmulewitz, R, Winters, C, Kephart, J, Harrison, MR, Martinez, E, Mundy, K, Halabi, S, and George, D. "Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial." United States. March 2017.
PMID
27862097
Source
pubmed
Published In
Prostate
Volume
77
Issue
4
Publish Date
2017
Start Page
385
End Page
395
DOI
10.1002/pros.23277

Prognostic and predictive biomarkers in metastatic castration-resistant prostate cancer.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Prognostic and predictive biomarkers in metastatic castration-resistant prostate cancer." Clinical Advances in Hematology & Oncology : H&O 15.3 (March 2017): 184-188.
PMID
28398272
Source
epmc
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
15
Issue
3
Publish Date
2017
Start Page
184
End Page
188

Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer.

Authors
Beer, TM; Armstrong, AJ; Rathkopf, D; Loriot, Y; Sternberg, CN; Higano, CS; Iversen, P; Evans, CP; Kim, C-S; Kimura, G; Miller, K; Saad, F; Bjartell, AS; Borre, M; Mulders, P; Tammela, TL; Parli, T; Sari, S; van Os, S; Theeuwes, A; Tombal, B
MLA Citation
Beer, TM, Armstrong, AJ, Rathkopf, D, Loriot, Y, Sternberg, CN, Higano, CS, Iversen, P, Evans, CP, Kim, C-S, Kimura, G, Miller, K, Saad, F, Bjartell, AS, Borre, M, Mulders, P, Tammela, TL, Parli, T, Sari, S, van Os, S, Theeuwes, A, and Tombal, B. "Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study." February 2017.
PMID
27477525
Source
epmc
Published In
European Urology
Volume
71
Issue
2
Publish Date
2017
Start Page
151
End Page
154
DOI
10.1016/j.eururo.2016.07.032

Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study

Authors
Beer, TM; Armstrong, AJ; Rathkopf, D; Loriot, Y; Sternberg, CN; Higano, CS; Iversen, P; Evans, CP; Kim, C-S; Kimura, G; Miller, K; Saad, F; Bjartell, AS; Borre, M; Mulders, P; Tammela, TL; Parli, T; Sari, S; van Os, S; Theeuwes, A; Tombal, B
MLA Citation
Beer, TM, Armstrong, AJ, Rathkopf, D, Loriot, Y, Sternberg, CN, Higano, CS, Iversen, P, Evans, CP, Kim, C-S, Kimura, G, Miller, K, Saad, F, Bjartell, AS, Borre, M, Mulders, P, Tammela, TL, Parli, T, Sari, S, van Os, S, Theeuwes, A, and Tombal, B. "Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study." EUROPEAN UROLOGY 71.2 (February 2017): 151-154.
Source
wos-lite
Published In
European Urology
Volume
71
Issue
2
Publish Date
2017
Start Page
151
End Page
154
DOI
10.1016/j.eururo.2016.07.032

Reply to M.A.N. Şendur et al and J. Michels.

Authors
Penson, DF; Armstrong, AJ; Concepcion, R; Agarwal, N; Olsson, C; Karsh, L; Dunshee, C; Wang, F; Wu, K; Krivoshik, A; Phung, D; Higano, CS
MLA Citation
Penson, DF, Armstrong, AJ, Concepcion, R, Agarwal, N, Olsson, C, Karsh, L, Dunshee, C, Wang, F, Wu, K, Krivoshik, A, Phung, D, and Higano, CS. "Reply to M.A.N. Şendur et al and J. Michels." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 35.1 (January 2017): 123-null. (Letter)
PMID
28034066
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
1
Publish Date
2017
Start Page
123
DOI
10.1200/jco.2016.69.9371

Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome.

Here we present, to the best of our knowledge, the first case of a paraneoplastic Cushing's syndrome (hypercortisolism) resulting from treatment-related neuroendocrine prostate cancer - a highly aggressive and difficult disease to treat. A 51-year-old man was started on androgen deprivation therapy after presenting with metastatic prostate cancer, characterized by diffuse osseous metastasis. Shortly thereafter, he developed progressive disease with biopsy proven neuroendocrine prostate cancer as well as symptoms of increased skin pigmentation, hypokalemia, hypertension, hyperglycemia and profound weakness, consistent with ectopic Cushing's syndrome. Molecular analysis of the patient's tumor through RNA sequencing showed high expression of several genes including CHGA, ASCL1, CALCA, HES6, PCSK1, CALCB and INSM1 confirming his neuroendocrine phenotype; elevated POMC expression was found, supporting the diagnosis of ectopic Cushing's syndrome.

Authors
Ramalingam, S; Eisenberg, A; Foo, WC; Freedman, J; Armstrong, AJ; Moss, LG; Harrison, MR
MLA Citation
Ramalingam, S, Eisenberg, A, Foo, WC, Freedman, J, Armstrong, AJ, Moss, LG, and Harrison, MR. "Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome." Int J Urol 23.12 (December 2016): 1038-1041.
PMID
27766686
Source
pubmed
Published In
Int J Urol
Volume
23
Issue
12
Publish Date
2016
Start Page
1038
End Page
1041
DOI
10.1111/iju.13225

Predictive medicine: Using circulating biomarkers to guide management of patients with genitourinary cancers.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Predictive medicine: Using circulating biomarkers to guide management of patients with genitourinary cancers." Urologic Oncology 34.11 (November 2016): 488-489.
PMID
27793467
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
34
Issue
11
Publish Date
2016
Start Page
488
End Page
489
DOI
10.1016/j.urolonc.2016.09.009

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer.

Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer.To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease.One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (<4 bone metastases; n=867), high-volume bone disease (≥4 bone metastases; n=850), lymph node only disease (n=195).Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy.Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc.Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14-0.22), visceral disease (HR, 0.28; 95% CI, 0.16-0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11-0.22; HR, 0.22; 95% CI, 0.16-0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04-0.19). For OS, HRs favored enzalutamide (<1) across all disease subgroups, although 95% CI was >1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease.Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease.Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy.

Authors
Evans, CP; Higano, CS; Keane, T; Andriole, G; Saad, F; Iversen, P; Miller, K; Kim, C-S; Kimura, G; Armstrong, AJ; Sternberg, CN; Loriot, Y; de Bono, J; Noonberg, SB; Mansbach, H; Bhattacharya, S; Perabo, F; Beer, TM; Tombal, B
MLA Citation
Evans, CP, Higano, CS, Keane, T, Andriole, G, Saad, F, Iversen, P, Miller, K, Kim, C-S, Kimura, G, Armstrong, AJ, Sternberg, CN, Loriot, Y, de Bono, J, Noonberg, SB, Mansbach, H, Bhattacharya, S, Perabo, F, Beer, TM, and Tombal, B. "The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer." European Urology 70.4 (October 2016): 675-683.
PMID
27006332
Source
epmc
Published In
European Urology
Volume
70
Issue
4
Publish Date
2016
Start Page
675
End Page
683
DOI
10.1016/j.eururo.2016.03.017

Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2.

Phenotypic plasticity involves a process in which cells transiently acquire phenotypic traits of another lineage. Two commonly studied types of phenotypic plasticity are epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In carcinomas, EMT drives invasion and metastatic dissemination, while MET is proposed to play a role in metastatic colonization. Phenotypic plasticity in sarcomas is not well studied; however, there is evidence that a subset of sarcomas undergo an MET-like phenomenon. While the exact mechanisms by which these transitions occur remain largely unknown, it is likely that some of the same master regulators that drive EMT and MET in carcinomas also act in sarcomas. In this study, we combined mathematical models with bench experiments to identify a core regulatory circuit that controls MET in sarcomas. This circuit comprises the microRNA 200 (miR-200) family, ZEB1, and GRHL2. Interestingly, combined expression of miR-200s and GRHL2 further upregulates epithelial genes to induce MET. This effect is phenocopied by downregulation of either ZEB1 or the ZEB1 cofactor, BRG1. In addition, an MET gene expression signature is prognostic for improved overall survival in sarcoma patients. Together, our results suggest that a miR-200, ZEB1, GRHL2 gene regulatory network may drive sarcoma cells to a more epithelial-like state and that this likely has prognostic relevance.

Authors
Somarelli, JA; Shetler, S; Jolly, MK; Wang, X; Bartholf Dewitt, S; Hish, AJ; Gilja, S; Eward, WC; Ware, KE; Levine, H; Armstrong, AJ; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Shetler, S, Jolly, MK, Wang, X, Bartholf Dewitt, S, Hish, AJ, Gilja, S, Eward, WC, Ware, KE, Levine, H, Armstrong, AJ, and Garcia-Blanco, MA. "Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2." Molecular and cellular biology 36.19 (October 2016): 2503-2513.
Website
http://hdl.handle.net/10161/13882
PMID
27402864
Source
epmc
Published In
Molecular and Cellular Biology
Volume
36
Issue
19
Publish Date
2016
Start Page
2503
End Page
2513
DOI
10.1128/mcb.00373-16

Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting.

While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.

Authors
Antonarakis, ES; Armstrong, AJ; Dehm, SM; Luo, J
MLA Citation
Antonarakis, ES, Armstrong, AJ, Dehm, SM, and Luo, J. "Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting." Prostate Cancer and Prostatic Diseases 19.3 (September 2016): 231-241. (Review)
PMID
27184811
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
3
Publish Date
2016
Start Page
231
End Page
241
DOI
10.1038/pcan.2016.17

Magnetic separation of acoustically focused cancer cells from blood for magnetographic templating and analysis.

Liquid biopsies hold enormous promise for the next generation of medical diagnoses. At the forefront of this effort, many are seeking to capture, enumerate and analyze circulating tumor cells (CTCs) as a means to prognosticate and develop individualized treatments for cancer. Capturing these rare cells, however, represents a major engineering challenge due to their low abundance, morphology and heterogeneity. A variety of microfluidic tools have been developed to isolate CTCs from drawn blood samples; however, few of these approaches offer a means to separate and analyze cells in an integrated system. We have developed a microfluidic platform comprised of three modules that offers high throughput separation of cancer cells from blood and on-chip organization of those cells for streamlined analyses. The first module uses an acoustic standing wave to rapidly align cells in a contact-free manner. The second module then separates magnetically labeled cells from unlabeled cells, offering purities exceeding 85% for cells and 90% for binary mixtures of synthetic particles. Finally, the third module contains a spatially periodic array of microwells with underlying micromagnets to capture individual cells for on-chip analyses (e.g., staining, imaging and quantification). This array is capable of capturing with accuracies exceeding 80% for magnetically labeled cells and 95% for magnetic particles. Overall, by virtue of its holistic processing of complex biological samples, this system has promise for the isolation and evaluation of rare cancer cells and can be readily extended to address a variety of applications across single cell biology and immunology.

Authors
Shields Iv, CW; Wang, JL; Ohiri, KA; Essoyan, ED; Yellen, BB; Armstrong, AJ; López, GP
MLA Citation
Shields Iv, CW, Wang, JL, Ohiri, KA, Essoyan, ED, Yellen, BB, Armstrong, AJ, and López, GP. "Magnetic separation of acoustically focused cancer cells from blood for magnetographic templating and analysis." Lab on a Chip 16.19 (September 2016): 3833-3844.
PMID
27713979
Source
epmc
Published In
Lab on a Chip
Volume
16
Issue
19
Publish Date
2016
Start Page
3833
End Page
3844
DOI
10.1039/c6lc00719h

Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways.

The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). Although there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post-transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET independent. Our results provide evidence for both MET-dependent and MET-independent metastatic pathways.

Authors
Somarelli, JA; Schaeffer, D; Marengo, MS; Bepler, T; Rouse, D; Ware, KE; Hish, AJ; Zhao, Y; Buckley, AF; Epstein, JI; Armstrong, AJ; Virshup, DM; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Schaeffer, D, Marengo, MS, Bepler, T, Rouse, D, Ware, KE, Hish, AJ, Zhao, Y, Buckley, AF, Epstein, JI, Armstrong, AJ, Virshup, DM, and Garcia-Blanco, MA. "Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways." Oncogene 35.33 (August 2016): 4302-4311.
Website
http://hdl.handle.net/10161/11682
PMID
26751776
Source
epmc
Published In
Oncogene
Volume
35
Issue
33
Publish Date
2016
Start Page
4302
End Page
4311
DOI
10.1038/onc.2015.497

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Authors
Ware, KE; Somarelli, JA; Schaeffer, D; Li, J; Zhang, T; Park, S; Patierno, SR; Freedman, J; Foo, W-C; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Ware, KE, Somarelli, JA, Schaeffer, D, Li, J, Zhang, T, Park, S, Patierno, SR, Freedman, J, Foo, W-C, Garcia-Blanco, MA, and Armstrong, AJ. "Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer." Oncotarget 7.31 (August 2016): 50507-50521.
Website
http://hdl.handle.net/10161/15123
PMID
27409172
Source
epmc
Published In
Oncotarget
Volume
7
Issue
31
Publish Date
2016
Start Page
50507
End Page
50521
DOI
10.18632/oncotarget.10476

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer.

Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit.Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point.In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain.In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

Authors
Sternberg, C; Armstrong, A; Pili, R; Ng, S; Huddart, R; Agarwal, N; Khvorostenko, D; Lyulko, O; Brize, A; Vogelzang, N; Delva, R; Harza, M; Thanos, A; James, N; Werbrouck, P; Bögemann, M; Hutson, T; Milecki, P; Chowdhury, S; Gallardo, E; Schwartsmann, G; Pouget, J-C; Baton, F; Nederman, T; Tuvesson, H; Carducci, M
MLA Citation
Sternberg, C, Armstrong, A, Pili, R, Ng, S, Huddart, R, Agarwal, N, Khvorostenko, D, Lyulko, O, Brize, A, Vogelzang, N, Delva, R, Harza, M, Thanos, A, James, N, Werbrouck, P, Bögemann, M, Hutson, T, Milecki, P, Chowdhury, S, Gallardo, E, Schwartsmann, G, Pouget, J-C, Baton, F, Nederman, T, Tuvesson, H, and Carducci, M. "Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer." August 2016.
PMID
27298414
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
22
Publish Date
2016
Start Page
2636
End Page
2643
DOI
10.1200/jco.2016.66.9697

Association Between RECIST Changes and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Receiving Docetaxel.

We explored the association between Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and 1.1 changes and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) from the control arms of the VENICE and MAINSAIL phase 3 trials, respectively, receiving docetaxel, prednisone, and placebo. We used Cox proportional hazards regression to evaluate the OS prognostic ability of RECIST changes after adjusting for prognostic factors. In the VENICE trial, the OS hazard ratio (HR) was 0.64 (95% confidence interval [CI] 0.42-0.99; p=0.045) for patients with a partial response (PR) compared to those without PR, and 1.78 (95% CI 1.07-2.95; p=0.026) for those with progressive disease (PD) compared to those without PD. After adjusting for prostate-specific antigen (PSA) changes, PD remained significant (HR 1.85, 95% CI 1.10-3.12; p=0.020). Data from the MAINSAIL trial corroborated the association of PR (HR 0.51, 95% CI 0.22-1.18; p=0.12) and PD (HR 3.51, 95% CI 1.92-6.43; p<0.001) with OS. After adjusting for PSA changes, PD was associated with poor OS (HR 2.36, 95% CI 1.11-5.04; p=0.026). Given the association between RECIST changes and OS, more frequent detection of measurable disease with current imaging techniques, and the poor reliability of bone scan and PSA changes, assessment of RECIST changes on treatment with novel agents in patients with measurable tumors may provide an objective signal of efficacy.In this study, we found an association between changes in objectively measurable tumors according to Response Evaluation Criteria in Solid Tumors (RECIST) and survival in patients with metastatic prostate cancer receiving docetaxel chemotherapy. Since bone scan and prostate-specific antigen changes are unreliable and measurable tumors are more frequently detected now because of better radiographic technology, a focus on RECIST changes should be considered during drug development to provide an objective signal of efficacy.

Authors
Sonpavde, G; Pond, GR; Templeton, AJ; Fandi, A; Tombal, B; Rosenthal, M; Armstrong, AJ; Petrylak, DP
MLA Citation
Sonpavde, G, Pond, GR, Templeton, AJ, Fandi, A, Tombal, B, Rosenthal, M, Armstrong, AJ, and Petrylak, DP. "Association Between RECIST Changes and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Receiving Docetaxel." European urology 69.6 (June 2016): 980-983.
PMID
26497922
Source
epmc
Published In
European Urology
Volume
69
Issue
6
Publish Date
2016
Start Page
980
End Page
983
DOI
10.1016/j.eururo.2015.10.008

Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial.

PURPOSE:Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC. PATIENTS AND METHODS:A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS). RESULTS:Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials. CONCLUSION:Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.

Authors
Penson, DF; Armstrong, AJ; Concepcion, R; Agarwal, N; Olsson, C; Karsh, L; Dunshee, C; Wang, F; Wu, K; Krivoshik, A; Phung, D; Higano, CS
MLA Citation
Penson, DF, Armstrong, AJ, Concepcion, R, Agarwal, N, Olsson, C, Karsh, L, Dunshee, C, Wang, F, Wu, K, Krivoshik, A, Phung, D, and Higano, CS. "Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 34.18 (June 2016): 2098-2106.
PMID
26811535
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
18
Publish Date
2016
Start Page
2098
End Page
2106
DOI
10.1200/jco.2015.64.9285

Development of a Novel c-MET-Based CTC Detection Platform.

UNLABELLED: Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors
Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Mol Cancer Res 14.6 (June 2016): 539-547.
Website
http://hdl.handle.net/10161/11944
PMID
26951228
Source
pubmed
Published In
Mol Cancer Res
Volume
14
Issue
6
Publish Date
2016
Start Page
539
End Page
547
DOI
10.1158/1541-7786.MCR-16-0011

Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer.

Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials.Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases.Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN-only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively.Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC.

Authors
Halabi, S; Kelly, WK; Ma, H; Zhou, H; Solomon, NC; Fizazi, K; Tangen, CM; Rosenthal, M; Petrylak, DP; Hussain, M; Vogelzang, NJ; Thompson, IM; Chi, KN; de Bono, J; Armstrong, AJ; Eisenberger, MA; Fandi, A; Li, S; Araujo, JC; Logothetis, CJ; Quinn, DI; Morris, MJ; Higano, CS; Tannock, IF; Small, EJ
MLA Citation
Halabi, S, Kelly, WK, Ma, H, Zhou, H, Solomon, NC, Fizazi, K, Tangen, CM, Rosenthal, M, Petrylak, DP, Hussain, M, Vogelzang, NJ, Thompson, IM, Chi, KN, de Bono, J, Armstrong, AJ, Eisenberger, MA, Fandi, A, Li, S, Araujo, JC, Logothetis, CJ, Quinn, DI, Morris, MJ, Higano, CS, Tannock, IF, and Small, EJ. "Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 34.14 (May 2016): 1652-1659.
PMID
26951312
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
14
Publish Date
2016
Start Page
1652
End Page
1659
DOI
10.1200/jco.2015.65.7270

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials.PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Authors
Scher, HI; Morris, MJ; Stadler, WM; Higano, C; Basch, E; Fizazi, K; Antonarakis, ES; Beer, TM; Carducci, MA; Chi, KN; Corn, PG; de Bono, JS; Dreicer, R; George, DJ; Heath, EI; Hussain, M; Kelly, WK; Liu, G; Logothetis, C; Nanus, D; Stein, MN; Rathkopf, DE; Slovin, SF; Ryan, CJ; Sartor, O; Small, EJ; Smith, MR; Sternberg, CN; Taplin, M-E; Wilding, G; Nelson, PS; Schwartz, LH; Halabi, S; Kantoff, PW; Armstrong, AJ; Prostate Cancer Clinical Trials Working Group 3,
MLA Citation
Scher, HI, Morris, MJ, Stadler, WM, Higano, C, Basch, E, Fizazi, K, Antonarakis, ES, Beer, TM, Carducci, MA, Chi, KN, Corn, PG, de Bono, JS, Dreicer, R, George, DJ, Heath, EI, Hussain, M, Kelly, WK, Liu, G, Logothetis, C, Nanus, D, Stein, MN, Rathkopf, DE, Slovin, SF, Ryan, CJ, Sartor, O, Small, EJ, Smith, MR, Sternberg, CN, Taplin, M-E, Wilding, G, Nelson, PS, Schwartz, LH, Halabi, S, Kantoff, PW, Armstrong, AJ, and Prostate Cancer Clinical Trials Working Group 3, . "Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 34.12 (April 2016): 1402-1418.
PMID
26903579
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
12
Publish Date
2016
Start Page
1402
End Page
1418
DOI
10.1200/jco.2015.64.2702

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT).This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time.Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years.Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Authors
Armstrong, AJ; Halabi, S; Healy, P; Lee, WR; Koontz, BF; Moul, JW; Mundy, K; Creel, P; Wood, S; Davis, K; Carducci, MA; Stein, M; Hobbs, C; Reimer, B; Nguyen, M; Anand, M; Bratt, L; Kim, S; Tran, PT; George, DJ; Department of Defense Prostate Cancer Clinical Trials Consortium,
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Lee, WR, Koontz, BF, Moul, JW, Mundy, K, Creel, P, Wood, S, Davis, K, Carducci, MA, Stein, M, Hobbs, C, Reimer, B, Nguyen, M, Anand, M, Bratt, L, Kim, S, Tran, PT, George, DJ, and Department of Defense Prostate Cancer Clinical Trials Consortium, . "A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy." March 2016.
PMID
26754260
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
1
Publish Date
2016
Start Page
100
End Page
106
DOI
10.1038/pcan.2015.59

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery.Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time.Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016).The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

Authors
Armstrong, AJ; Healy, P; Halabi, S; Vollmer, R; Lark, A; Kemeny, G; Ware, K; Freedland, SJ
MLA Citation
Armstrong, AJ, Healy, P, Halabi, S, Vollmer, R, Lark, A, Kemeny, G, Ware, K, and Freedland, SJ. "Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer." Prostate Cancer and Prostatic Diseases 19.1 (March 2016): 40-45.
Website
http://hdl.handle.net/10161/10917
PMID
26458958
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
1
Publish Date
2016
Start Page
40
End Page
45
DOI
10.1038/pcan.2015.46

Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.

Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.Novartis and Pfizer.

Authors
Armstrong, AJ; Halabi, S; Eisen, T; Broderick, S; Stadler, WM; Jones, RJ; Garcia, JA; Vaishampayan, UN; Picus, J; Hawkins, RE; Hainsworth, JD; Kollmannsberger, CK; Logan, TF; Puzanov, I; Pickering, LM; Ryan, CW; Protheroe, A; Lusk, CM; Oberg, S; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Eisen, T, Broderick, S, Stadler, WM, Jones, RJ, Garcia, JA, Vaishampayan, UN, Picus, J, Hawkins, RE, Hainsworth, JD, Kollmannsberger, CK, Logan, TF, Puzanov, I, Pickering, LM, Ryan, CW, Protheroe, A, Lusk, CM, Oberg, S, and George, DJ. "Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial." The Lancet. Oncology 17.3 (March 2016): 378-388.
PMID
26794930
Source
epmc
Published In
The Lancet. Oncology
Volume
17
Issue
3
Publish Date
2016
Start Page
378
End Page
388
DOI
10.1016/s1470-2045(15)00515-x

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy

Authors
Armstrong, AJ; Halabi, S; Healy, P; Lee, WR; Koontz, BF; Moul, JW; Mundy, K; Creel, P; Wood, S; Davis, K; Carducci, MA; Stein, M; Hobbs, C; Reimer, B; Nguyen, M; Anand, M; Bratt, L; Kim, S; Tran, PT; George, DJ; Tr, DDPCC
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Lee, WR, Koontz, BF, Moul, JW, Mundy, K, Creel, P, Wood, S, Davis, K, Carducci, MA, Stein, M, Hobbs, C, Reimer, B, Nguyen, M, Anand, M, Bratt, L, Kim, S, Tran, PT, George, DJ, and Tr, DDPCC. "A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy." PROSTATE CANCER AND PROSTATIC DISEASES 19.1 (March 2016): 100-106.
Source
wos-lite
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
1
Publish Date
2016
Start Page
100
End Page
106
DOI
10.1038/pcan.2015.59

Management of Prostate Cancer in the Elderly.

The impact of localized prostate cancer in the elderly depends on disease aggressiveness and life expectancy. In men with localized prostate cancer, those with low-risk disease or a shorter life expectancy should be managed expectantly, whereas those with long life expectancy or more aggressive disease may benefit from curative treatment. Comorbidity and quality-of-life concerns are key considerations during the selection of therapeutic modalities in the elderly in localized and metastatic settings. A variety of new agents have changed the therapeutic landscape in castrate-resistant prostate cancer, but their benefits need to be considered alongside their side effects and cost.

Authors
Tay, KJ; Moul, JW; Armstrong, AJ
MLA Citation
Tay, KJ, Moul, JW, and Armstrong, AJ. "Management of Prostate Cancer in the Elderly." Clinics in Geriatric Medicine 32.1 (February 2016): 113-132. (Review)
PMID
26614864
Source
epmc
Published In
Clinics in Geriatric Medicine
Volume
32
Issue
1
Publish Date
2016
Start Page
113
End Page
132
DOI
10.1016/j.cger.2015.08.001

Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL.

Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial.PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged <75 years was pre-specified for the coprimary end points and adverse events (AEs).Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7-not yet reached] versus 25.1 months (95% CI 22.6-28.0); hazard ratio (HR) = 0.61 (95% CI 0.47-0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3-not yet reached) versus 3.7 months (95% CI 3.6-5.3); HR = 0.17 (95% CI 0.12-0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)].Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls.NCT01212991, ClinicalTrials.gov.

Authors
Graff, JN; Baciarello, G; Armstrong, AJ; Higano, CS; Iversen, P; Flaig, TW; Forer, D; Parli, T; Phung, D; Tombal, B; Beer, TM; Sternberg, CN
MLA Citation
Graff, JN, Baciarello, G, Armstrong, AJ, Higano, CS, Iversen, P, Flaig, TW, Forer, D, Parli, T, Phung, D, Tombal, B, Beer, TM, and Sternberg, CN. "Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL." Annals of Oncology : Official Journal of the European Society for Medical Oncology 27.2 (February 2016): 286-294.
PMID
26578735
Source
epmc
Published In
Annals of Oncology
Volume
27
Issue
2
Publish Date
2016
Start Page
286
End Page
294
DOI
10.1093/annonc/mdv542

Tasquinimod in the treatment of castrate-resistant prostate cancer - current status and future prospects.

Treatment options have significantly expanded in recent years for men with metastatic castration-resistant prostate cancer (mCRPC), with the routine use of immunotherapy (sipuleucel-T) and novel hormonal agents such as enzalutamide and abiraterone acetate prior to taxane-based chemotherapy or radium-223 radiotherapy. A number of immune checkpoints limit the immune response of the host to metastatic tumor progression in prostate cancer, one of which is an immunosuppressive and pro-angiogenic cell called the myeloid-derived suppressor cell (MDSC). Tasquinimod is a small molecular oral inhibitor of S100A9, a key cell surface regulator of MDSC function, and has shown anti-angiogenic, antitumor and immune-modulatory properties in preclinical models of prostate cancer and other solid tumors. A large randomized phase II trial of tasquinimod in men with chemotherapy-naïve mCRPC demonstrated a significant prolongation in radiographic and symptomatic progression-free survival compared with placebo, which was also associated with improvements in overall survival. Tasquinimod was studied in a global phase III randomized trial in men with bone mCRPC and, while it significantly improved radiographic progression-free survival, this did not result in an overall survival benefit. However, tasquinimod is under evaluation as well as a combination therapy with other systemic agents in prostate cancer and as a single agent in other solid tumors. This review encompasses the preclinical and clinical development of tasquinimod as a therapy for men with prostate cancer.

Authors
Mehta, AR; Armstrong, AJ
MLA Citation
Mehta, AR, and Armstrong, AJ. "Tasquinimod in the treatment of castrate-resistant prostate cancer - current status and future prospects." Therapeutic Advances in Urology 8.1 (February 2016): 9-18. (Review)
PMID
26834836
Source
epmc
Published In
Therapeutic Advances in Urology
Volume
8
Issue
1
Publish Date
2016
Start Page
9
End Page
18
DOI
10.1177/1756287215603558

Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).

Authors
George, DJ; Halabi, S; Healy, P; Gemberling, S; Winters, C; Mundy, K; Harrison, MR; Szmulewitz, RZ; Armstrong, AJ
MLA Citation
George, DJ, Halabi, S, Healy, P, Gemberling, S, Winters, C, Mundy, K, Harrison, MR, Szmulewitz, RZ, and Armstrong, AJ. "Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC)." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
275
End Page
275
DOI
10.1200/jco.2016.34.2_suppl.275

Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC).

Authors
Penson, DF; Armstrong, AJ; Concepcion, RS; Wu, K; Wang, F; Krivoshik, AP; Phung, D; Higano, CS
MLA Citation
Penson, DF, Armstrong, AJ, Concepcion, RS, Wu, K, Wang, F, Krivoshik, AP, Phung, D, and Higano, CS. "Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC)." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
169
End Page
169
DOI
10.1200/jco.2016.34.2_suppl.169

Analysis of the PROCEED registry by baseline prostate-specific antigen (PSA) quartiles: Preliminary analysis of real-world sipuleucel-T (sip-T) use.

Authors
Higano, CS; Armstrong, AJ; Cooperberg, MR; Concepcion, RS; Tutrone, RF; Olsson, CA; Pieczonka, CM; Shore, ND; Chang, NN; LIll, JS; Sartor, AO
MLA Citation
Higano, CS, Armstrong, AJ, Cooperberg, MR, Concepcion, RS, Tutrone, RF, Olsson, CA, Pieczonka, CM, Shore, ND, Chang, NN, LIll, JS, and Sartor, AO. "Analysis of the PROCEED registry by baseline prostate-specific antigen (PSA) quartiles: Preliminary analysis of real-world sipuleucel-T (sip-T) use." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
193
End Page
193
DOI
10.1200/jco.2016.34.2_suppl.193

Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry.

Authors
Armstrong, AJ; Higano, CS; Sartor, AO; Vogelzang, NJ; Berry, WR; Penson, DF; Kassabian, V; Nordquist, LT; Chang, NN; LIll, JS; Cooperberg, MR
MLA Citation
Armstrong, AJ, Higano, CS, Sartor, AO, Vogelzang, NJ, Berry, WR, Penson, DF, Kassabian, V, Nordquist, LT, Chang, NN, LIll, JS, and Cooperberg, MR. "Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
320
End Page
320
DOI
10.1200/jco.2016.34.2_suppl.320

Surrogacy analysis of prostate-specific antigen (PSA) decline for improved overall survival (OS) with enzalutamide (ENZ) in AFFIRM.

Authors
Armstrong, AJ; Saad, F; Shore, ND; Fizazi, K; Phung, D; Dmuchowski, CF; Hirmand, M; Forer, D; Scher, HI; De Bono, JS
MLA Citation
Armstrong, AJ, Saad, F, Shore, ND, Fizazi, K, Phung, D, Dmuchowski, CF, Hirmand, M, Forer, D, Scher, HI, and De Bono, JS. "Surrogacy analysis of prostate-specific antigen (PSA) decline for improved overall survival (OS) with enzalutamide (ENZ) in AFFIRM." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
266
End Page
266
DOI
10.1200/jco.2016.34.2_suppl.266

Correlation between radiographic progression-free survival (rPFS) and overall survival (OS): Results from PREVAIL.

Authors
Morris, MJ; Beer, TM; Loriot, Y; Higano, CS; Armstrong, AJ; Sternberg, CN; De Bono, JS; Tombal, BF; Parli, T; Bhattacharya, S; Krivoshik, AP; Phung, D; Rathkopf, DE
MLA Citation
Morris, MJ, Beer, TM, Loriot, Y, Higano, CS, Armstrong, AJ, Sternberg, CN, De Bono, JS, Tombal, BF, Parli, T, Bhattacharya, S, Krivoshik, AP, Phung, D, and Rathkopf, DE. "Correlation between radiographic progression-free survival (rPFS) and overall survival (OS): Results from PREVAIL." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
182
End Page
182
DOI
10.1200/jco.2016.34.2_suppl.182

A Phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castration-resistant prostate cancer (mCRPC), secondary endpoints.

Authors
Sternberg, CN; Armstrong, AJ; Pili, R; Nederman, T; Carducci, MA
MLA Citation
Sternberg, CN, Armstrong, AJ, Pili, R, Nederman, T, and Carducci, MA. "A Phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castration-resistant prostate cancer (mCRPC), secondary endpoints." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
239
End Page
239
DOI
10.1200/jco.2016.34.2_suppl.239

Real-world experience of therapeutic sequencing and time to first anticancer intervention (ACI) following sipuleucel-T (sip-T): Initial data from the PROCEED registry.

Authors
Sartor, AO; Cooperberg, MR; Armstrong, AJ; Vogelzang, NJ; Vacirca, JL; Scholz, MC; Dakhil, SR; Nordquist, LT; Heath, EI; Chang, NN; LIll, JS; Higano, CS
MLA Citation
Sartor, AO, Cooperberg, MR, Armstrong, AJ, Vogelzang, NJ, Vacirca, JL, Scholz, MC, Dakhil, SR, Nordquist, LT, Heath, EI, Chang, NN, LIll, JS, and Higano, CS. "Real-world experience of therapeutic sequencing and time to first anticancer intervention (ACI) following sipuleucel-T (sip-T): Initial data from the PROCEED registry." January 10, 2016.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
2_suppl
Publish Date
2016
Start Page
194
End Page
194
DOI
10.1200/jco.2016.34.2_suppl.194

Clinical Utility of Circulating Tumor Cells in Advanced Prostate Cancer.

Men with metastatic castration-resistant prostate cancer (mCRPC) frequently have circulating tumor cells (CTCs) that are detectable in their peripheral blood. The CellSearch® method of enumerating CTCs is presently the only FDA-cleared CTC test available clinically for men with mCRPC and has been shown to have prognostic significance in this setting, both before and during systemic therapy. Clinical utility, reflecting the ability of this test to favorably change outcomes, is a more controversial and higher bar. The CellSearch® CTC assay can provide updated prognostic and potentially surrogate information in specific clinical scenarios and in clinical trials, but formal randomized trials of clinical utility remain an unmet clinical need. Recent data suggest that CTCs may harbor genetic information (such as the androgen receptor splice variant 7, AR-V7) relevant to changing clinical management and predicting treatment sensitivity or resistance to cancer therapies such as enzalutamide, abiraterone, and taxane chemotherapies. Further molecular characterization of CTCs, cell-free DNA, or RNA can also provide additional information that may have clinical utility. Thus, CTC research is moving toward predictive medicine, based on the biologic characterization and improvements in clinical outcomes associated with heterogeneous cell types both within and between patients.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Clinical Utility of Circulating Tumor Cells in Advanced Prostate Cancer." Current oncology reports 18.1 (January 2016): 3-. (Review)
PMID
26700506
Source
epmc
Published In
Current Oncology Reports
Volume
18
Issue
1
Publish Date
2016
Start Page
3
DOI
10.1007/s11912-015-0490-9

Prostate Cancer, Version 1.2016.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

Authors
Mohler, JL; Armstrong, AJ; Bahnson, RR; D'Amico, AV; Davis, BJ; Eastham, JA; Enke, CA; Farrington, TA; Higano, CS; Horwitz, EM; Hurwitz, M; Kane, CJ; Kawachi, MH; Kuettel, M; Lee, RJ; Meeks, JJ; Penson, DF; Plimack, ER; Pow-Sang, JM; Raben, D; Richey, S; Roach, M; Rosenfeld, S; Schaeffer, E; Skolarus, TA; Small, EJ; Sonpavde, G; Srinivas, S; Strope, SA; Tward, J; Shead, DA; Freedman-Cass, DA
MLA Citation
Mohler, JL, Armstrong, AJ, Bahnson, RR, D'Amico, AV, Davis, BJ, Eastham, JA, Enke, CA, Farrington, TA, Higano, CS, Horwitz, EM, Hurwitz, M, Kane, CJ, Kawachi, MH, Kuettel, M, Lee, RJ, Meeks, JJ, Penson, DF, Plimack, ER, Pow-Sang, JM, Raben, D, Richey, S, Roach, M, Rosenfeld, S, Schaeffer, E, Skolarus, TA, Small, EJ, Sonpavde, G, Srinivas, S, Strope, SA, Tward, J, Shead, DA, and Freedman-Cass, DA. "Prostate Cancer, Version 1.2016." Journal of the National Comprehensive Cancer Network : Jnccn 14.1 (January 2016): 19-30.
PMID
26733552
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
14
Issue
1
Publish Date
2016
Start Page
19
End Page
30
DOI
10.6004/jnccn.2016.0004

Prostate Cancer, Version 1.2016 Featured Updates to the NCCN Guidelines

Authors
Mohler, JL; Armstrong, AJ; Bahnson, RR; D'Amico, AV; Davis, BJ; Eastham, JA; Enke, CA; Farrington, TA; Higano, CS; Horwitz, EM; Hurwitz, M; Kane, CJ; Kawachi, MH; Kuettel, M; Lee, RJ; Meeks, JJ; Penson, DF; Plimack, ER; Pow-Sang, JM; Raben, D; Richey, S; III, RM; Rosenfeld, S; Schaeffer, E; Skolarus, TA; Small, EJ; Sonpavde, G; Srinivas, S; Strope, SA; Tward, J; Shead, DA; Freedman-Cass, DA
MLA Citation
Mohler, JL, Armstrong, AJ, Bahnson, RR, D'Amico, AV, Davis, BJ, Eastham, JA, Enke, CA, Farrington, TA, Higano, CS, Horwitz, EM, Hurwitz, M, Kane, CJ, Kawachi, MH, Kuettel, M, Lee, RJ, Meeks, JJ, Penson, DF, Plimack, ER, Pow-Sang, JM, Raben, D, Richey, S, III, RM, Rosenfeld, S, Schaeffer, E, Skolarus, TA, Small, EJ, Sonpavde, G, Srinivas, S, Strope, SA, Tward, J, Shead, DA, and Freedman-Cass, DA. "Prostate Cancer, Version 1.2016 Featured Updates to the NCCN Guidelines." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 14.1 (January 2016): 19-30.
Source
wos-lite
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
14
Issue
1
Publish Date
2016
Start Page
19
End Page
30
DOI
10.6004/jnccn.2016.0004

Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch.

Notch signaling is implicated in prostate cancer progression and docetaxel resistance. Cui and colleagues describe the additive efficacy and mechanisms of a γ-secretase inhibitor, PF-03084014, and docetaxel in preclinical models of prostate cancer, suggesting the need for further clinical development of Notch pathway modulators in men with metastatic prostate cancer.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch." Clinical cancer research : an official journal of the American Association for Cancer Research 21.20 (October 2015): 4505-4507.
Website
http://hdl.handle.net/10161/10916
PMID
26307134
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
21
Issue
20
Publish Date
2015
Start Page
4505
End Page
4507
DOI
10.1158/1078-0432.ccr-15-1613

A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer.

Cixutumumab, a human monoclonal antibody (HuMAb), targets the insulin-like growth factor receptor. Ramucirumab is a recombinant HuMAb that binds to vascular endothelial growth factor receptor-2. A non-comparative randomised phase II study evaluated cixutumumab or ramucirumab plus mitoxantrone and prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC).Men with progressive mCRPC during or after docetaxel therapy received mitoxantrone 12 mg/m(2) on day 1 and prednisone 5mg twice daily and were randomised 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary end-point was composite progression-free survival (cPFS). Secondary end-points included safety, response, radiographic progression-free survival (PFS) and overall survival (OS). Sample size was based on a 50% increase in median cPFS from 2.6 (MP) to 3.9 months (either combination).132 men were treated (66 per arm). Median cPFS was 4.1 months (95% confidence interval (CI), 2.2-5.6) for cixutumumab and 6.7 months (95% CI, 4.5-8.3) for ramucirumab. Median time to radiographic progression was 7.5 months for cixutumumab and 10.2 months for ramucirumab, with a median OS of 10.8 and 13.0 months, respectively. Fatigue was the most frequent adverse event (AE). Incidence of most non-haematologic grade 3-4 AEs was <10% on both arms. Grade 3 cardiac dysfunction occurred in 7.6% of patients on ramucirumab.Combinations of cixutumumab or ramucirumab plus MP were feasible and associated with moderate toxicities in docetaxel-pretreated men with mCRPC. Of the two regimens, the ramucirumab regimen is worthy of further testing based on the observed cPFS relative to the historical control.

Authors
Hussain, M; Rathkopf, D; Liu, G; Armstrong, A; Kelly, WK; Ferrari, A; Hainsworth, J; Joshi, A; Hozak, RR; Yang, L; Schwartz, JD; Higano, CS
MLA Citation
Hussain, M, Rathkopf, D, Liu, G, Armstrong, A, Kelly, WK, Ferrari, A, Hainsworth, J, Joshi, A, Hozak, RR, Yang, L, Schwartz, JD, and Higano, CS. "A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer." European journal of cancer (Oxford, England : 1990) 51.13 (September 2015): 1714-1724.
PMID
26082390
Source
epmc
Published In
European Journal of Cancer
Volume
51
Issue
13
Publish Date
2015
Start Page
1714
End Page
1724
DOI
10.1016/j.ejca.2015.05.019

Abstract 1847: AR-V7 regulation during epithelial plasticity

Authors
Ware, KE; Schaeffer, D; Zhang, T; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Ware, KE, Schaeffer, D, Zhang, T, Garcia-Blanco, MA, and Armstrong, AJ. "Abstract 1847: AR-V7 regulation during epithelial plasticity." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
1847
End Page
1847
DOI
10.1158/1538-7445.AM2015-1847

Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel. PATIENTS AND METHODS: We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy. RESULTS: There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group. CONCLUSION: In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Authors
Zhang, T; Dhawan, MS; Healy, P; George, DJ; Harrison, MR; Oldan, J; Chin, B; Armstrong, AJ
MLA Citation
Zhang, T, Dhawan, MS, Healy, P, George, DJ, Harrison, MR, Oldan, J, Chin, B, and Armstrong, AJ. "Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer." Clin Genitourin Cancer 13.4 (August 2015): 392-399.
PMID
25708161
Source
pubmed
Published In
Clin Genitourin Cancer
Volume
13
Issue
4
Publish Date
2015
Start Page
392
End Page
399
DOI
10.1016/j.clgc.2015.01.004

A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND:Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC. METHODS:We conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose. RESULTS:A total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure. CONCLUSION:Combined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort.

Authors
Kanesvaran, R; Watt, K; Turnbull, JD; Armstrong, AJ; Wolkowiez, MC; George, DJ
MLA Citation
Kanesvaran, R, Watt, K, Turnbull, JD, Armstrong, AJ, Wolkowiez, MC, and George, DJ. "A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma." Clinical Genitourinary Cancer 13.4 (August 2015): 319-327.
PMID
26174223
Source
epmc
Published In
Clinical Genitourinary Cancer
Volume
13
Issue
4
Publish Date
2015
Start Page
319
End Page
327
DOI
10.1016/j.clgc.2014.12.011

Docetaxel for advanced prostate cancer: how early to start?

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Docetaxel for advanced prostate cancer: how early to start?." The Lancet. Oncology 16.7 (July 2015): 741-742.
PMID
26028517
Source
epmc
Published In
The Lancet. Oncology
Volume
16
Issue
7
Publish Date
2015
Start Page
741
End Page
742
DOI
10.1016/s1470-2045(15)00012-1

Cytotoxic chemotherapy in the contemporary management of metastatic castration-resistant prostate cancer (mCRPC).

For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long-term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration-sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies.

Authors
Sonpavde, G; Wang, CG; Galsky, MD; Oh, WK; Armstrong, AJ
MLA Citation
Sonpavde, G, Wang, CG, Galsky, MD, Oh, WK, and Armstrong, AJ. "Cytotoxic chemotherapy in the contemporary management of metastatic castration-resistant prostate cancer (mCRPC)." Bju International 116.1 (July 2015): 17-29. (Review)
PMID
25046451
Source
epmc
Published In
Bju International
Volume
116
Issue
1
Publish Date
2015
Start Page
17
End Page
29
DOI
10.1111/bju.12867

Carcinosarcomas: tumors in transition?

Carcinosarcomas are rare, biphasic tumors that are comprised of carcinomatous and sarcomatous elements. While the exact mechanism by which these two phenotypes arise within a single tumor remains unclear, molecular evidence indicates that the epitheliod and spindle-cell components share a clonal origin. We propose that the biphasic nature of these neoplasms may represent an extreme case of epithelial plasticity, in which an epithelial-like cell undergoes a transition to a more mesenchymal phenotype. The present review will discuss both the histological and molecular biological evidence of the involvement of epithelial plasticity in driving the mixed phenotypes observed in carcinosarcomas.

Authors
Somarelli, JA; Boss, M-K; Epstein, JI; Armstrong, AJ; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Boss, M-K, Epstein, JI, Armstrong, AJ, and Garcia-Blanco, MA. "Carcinosarcomas: tumors in transition?." Histology and histopathology 30.6 (June 2015): 673-687. (Review)
PMID
25587806
Source
epmc
Published In
Histology and Histopathology
Volume
30
Issue
6
Publish Date
2015
Start Page
673
End Page
687
DOI
10.14670/hh-30.673

Reversal of PSA progression on abiraterone acetate through the administration with food in men with metastatic castration-resistant prostate cancer.

Owing to efficacy and tolerability, abiraterone acetate (AA) is a leading treatment for men with metastatic castration-resistant prostate cancer. Increased serum concentrations of AA, such as by taking AA with food, may lead to the inhibition of additional enzymes in the androgen synthesis pathway implicated in castration-resistant prostate cancer progression.Medical records of men with metastatic castration-resistant prostate cancer (mCRPC) who received AA between 1 April 2011 and 31 December 2013 were retrospectively reviewed. The primary outcome was the percent of men with a rising PSA on AA who experienced any PSA decline within 3 months after changing the administration of AA from without food to with food. Secondary outcomes were median time on AA therapy in men who received AA therapy without food versus those that switched administration from without food to with food at PSA progression, and the percent of men who experienced any decline in serum testosterone concentration, and the rate of adverse events observed while taking AA with food.Nineteen men who switched AA administration from without food to with food and 41 patients who administered AA without food only were included in the study. Of those patients who took AA with food at PSA progression, a PSA decline was observed in 3 of the 19 (16%) men, including 3 of the 14 men who had an initial response to AA (21%). Testosterone declined in five out of seven patients from pre-food levels. The median time on AA therapy was increased by nearly 100 days in patients who switched AA administration from without food to with food. No increases in toxicity were observed.Some men with mCRPC may benefit from taking AA with food. Further prospective comparative studies are needed to determine if changing AA administration is beneficial.

Authors
Stover, JT; Moore, RA; Davis, K; Harrison, MR; Armstrong, AJ
MLA Citation
Stover, JT, Moore, RA, Davis, K, Harrison, MR, and Armstrong, AJ. "Reversal of PSA progression on abiraterone acetate through the administration with food in men with metastatic castration-resistant prostate cancer." Prostate Cancer and Prostatic Diseases 18.2 (June 2015): 161-166.
PMID
25777155
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
18
Issue
2
Publish Date
2015
Start Page
161
End Page
166
DOI
10.1038/pcan.2015.7

Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution.

BACKGROUND: Sipuleucel-T, an autologous cellular immunotherapy, is approved for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first personalized treatment for prostate cancer to be manufactured using the immune system of each individual patient. Patient preparation and compliance are critical because patients undergo serial leukapheresis and reinfusion procedures within a relatively short time period, which may result in transient reactions. OBJECTIVES: The study aims to identify patients best suited for sipuleucel-T treatment, provide an overview of treatment, and encourage infusion sites to consider a primary contact model for the efficient coordination of care. METHODS: Treatment experiences were evaluated from 124 patients with mCRPC who received sipuleucel-T from January 2010 to August 2013 according to current best practices. Feedback was collected from reflective interdisciplinary discussion within the sipuleucel-T delivery team (nurses, advanced practice providers, urologists, and medical oncologists). FINDINGS: Early patient identification and education on treatment rationale, delivery, and expectations help ensure a successful sipuleucel-T treatment experience. A multidisciplinary coordinated-care process can facilitate proficient sipuleucel-T delivery, and the selection of a primary contact for care coordination offers benefits, such as clear and efficient education.

Authors
Davis, K; Wood, S; Dill, E; Fesko, Y; Bitting, RL; Harrison, MR; Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Davis, K, Wood, S, Dill, E, Fesko, Y, Bitting, RL, Harrison, MR, Armstrong, AJ, Moul, JW, and George, DJ. "Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution." Clin J Oncol Nurs 19.3 (June 2015): 297-303.
PMID
26000580
Source
pubmed
Published In
Clin J Oncol Nurs
Volume
19
Issue
3
Publish Date
2015
Start Page
297
End Page
303
DOI
10.1188/15.CJON.297-303

Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN)

Authors
Armstrong, AJ; Broderick, S; Eisen, T; Stadler, WM; Jones, RJ; Garcia, JA; Vaishampayan, UN; Picus, J; Hawkins, RE; Hainsworth, JD; Kollmannsberger, CK; Logan, TF; Puzanov, I; Pickering, LM; Ryan, CW; Protheroe, A; Lusk, CM; Oberg, S; Halabi, S; George, DJ
MLA Citation
Armstrong, AJ, Broderick, S, Eisen, T, Stadler, WM, Jones, RJ, Garcia, JA, Vaishampayan, UN, Picus, J, Hawkins, RE, Hainsworth, JD, Kollmannsberger, CK, Logan, TF, Puzanov, I, Pickering, LM, Ryan, CW, Protheroe, A, Lusk, CM, Oberg, S, Halabi, S, and George, DJ. "Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies.

Authors
Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; George, DJ; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, George, DJ, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC).

Authors
Scher, HI; Morris, MJ; Stadler, WM; Higano, CS; Halabi, S; Smith, MR; Basch, EM; Fizazi, K; Ryan, CJ; Antonarakis, ES; Corn, PG; Liu, G; De Bono, JS; Schwartz, LH; Beer, TM; Kelly, WK; Hussain, M; Sartor, AO; Kantoff, PW; Armstrong, AJ
MLA Citation
Scher, HI, Morris, MJ, Stadler, WM, Higano, CS, Halabi, S, Smith, MR, Basch, EM, Fizazi, K, Ryan, CJ, Antonarakis, ES, Corn, PG, Liu, G, De Bono, JS, Schwartz, LH, Beer, TM, Kelly, WK, Hussain, M, Sartor, AO, Kantoff, PW, and Armstrong, AJ. "The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Administration of sipuleucel-T (sip-T) infusions (infs) outside of the clinical trial setting: Data from the PROCEED registry.

Authors
Higano, CS; Sartor, AO; Vogelzang, NJ; Dakhil, SR; Concepcion, RS; Pieczonka, CM; Vacirca, JL; Tutrone, RF; Olsson, CA; Penson, DF; Biggs, C; Lill, JS; Gray, TE; McCoy, C; Cooperberg, MR; Armstrong, AJ
MLA Citation
Higano, CS, Sartor, AO, Vogelzang, NJ, Dakhil, SR, Concepcion, RS, Pieczonka, CM, Vacirca, JL, Tutrone, RF, Olsson, CA, Penson, DF, Biggs, C, Lill, JS, Gray, TE, McCoy, C, Cooperberg, MR, and Armstrong, AJ. "Administration of sipuleucel-T (sip-T) infusions (infs) outside of the clinical trial setting: Data from the PROCEED registry." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy.

Authors
Li, J; Beaver, J; Bitting, RL; Gregory, S; Armstrong, AJ
MLA Citation
Li, J, Beaver, J, Bitting, RL, Gregory, S, and Armstrong, AJ. "Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Efficacy analysis of a phase III study of androgen deprivation therapy (ADT) +/- docetaxel (D) for men with biochemical relapse (BCR) after prostatectomy.

Authors
Morris, MJ; Hilden, P; Gleave, ME; Armstrong, AJ; Carducci, MA; Saad, F; Dayan, ES; Filipenko, J; Acosta, I; Heller, G; Scher, HI
MLA Citation
Morris, MJ, Hilden, P, Gleave, ME, Armstrong, AJ, Carducci, MA, Saad, F, Dayan, ES, Filipenko, J, Acosta, I, Heller, G, and Scher, HI. "Efficacy analysis of a phase III study of androgen deprivation therapy (ADT) +/- docetaxel (D) for men with biochemical relapse (BCR) after prostatectomy." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

New treatment options in castration-resistant prostate cancer.

Most of the updates in the 2015 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer center on the systemic therapy front, with a host of newer agents in the mix. At the NCCN 20th Annual Conference, Dr. Andrew J. Armstrong discussed some of the key developments in metastatic castration-resistant and castration-sensitive prostate cancer, particularly the conflicting results on repurposing docetaxel in castration-sensitive disease, the specific population who may experience greater survival benefit from immunotherapy in castration-resistant disease, updated data on the use of androgen receptor and biosynthesis inhibitors, and the emerging role of AR-V7 (androgen-receptor splice variant 7 messenger RNA) as a biomarker of treatment response.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "New treatment options in castration-resistant prostate cancer." Journal of the National Comprehensive Cancer Network : Jnccn 13.5 Suppl (May 2015): 690-693.
PMID
25995432
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
13
Issue
5 Suppl
Publish Date
2015
Start Page
690
End Page
693
DOI
10.6004/jnccn.2015.0205

New Treatment Options in Castration-Resistant Prostate Cancer

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "New Treatment Options in Castration-Resistant Prostate Cancer." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 13.5.5 (May 2015): 690-693.
Source
wos-lite
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
13
Issue
5.5
Publish Date
2015
Start Page
690
End Page
693
DOI
10.6004/jnccn.2015.0205

Counterpoints: Which should be used first in symptomatic metastatic castration-resistant prostate cancer, docetaxel or radium? Radium-223 is the preferred therapy in bone-predominant symptomatic metastatic castration-resistant prostate cancer.

Authors
Li, J; Armstrong, AJ
MLA Citation
Li, J, and Armstrong, AJ. "Counterpoints: Which should be used first in symptomatic metastatic castration-resistant prostate cancer, docetaxel or radium? Radium-223 is the preferred therapy in bone-predominant symptomatic metastatic castration-resistant prostate cancer." Clinical advances in hematology & oncology : H&O 13.5 (May 2015): 293-298.
PMID
26352773
Source
epmc
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
13
Issue
5
Publish Date
2015
Start Page
293
End Page
298

Making progress on progression in metastatic prostate cancer.

Authors
Armstrong, AJ; Halabi, S
MLA Citation
Armstrong, AJ, and Halabi, S. "Making progress on progression in metastatic prostate cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.12 (April 2015): 1322-1324.
PMID
25667271
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
12
Publish Date
2015
Start Page
1322
End Page
1324
DOI
10.1200/jco.2014.59.4283

Burden of disease matters when it comes to systemic therapy for prostate cancer

Authors
Harrison, MR; Armstrong, AJ
MLA Citation
Harrison, MR, and Armstrong, AJ. "Burden of disease matters when it comes to systemic therapy for prostate cancer." European Urology 67.3 (March 1, 2015): 448-450.
Source
scopus
Published In
European Urology
Volume
67
Issue
3
Publish Date
2015
Start Page
448
End Page
450
DOI
10.1016/j.eururo.2014.02.032

Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer

© 2015 Elsevier Inc. Background: The presence of ≥5 circulating tumor cells (CTCs) is prognostic for shorter survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, some men have low CTCs despite widespread disease, suggesting heterogeneity in CTC phenotype or detection. The aim of this study was to evaluate the association of CTC enumeration with clinical disease characteristics and overall survival in men with mCRPC at our institution. Design: CTCs were enumerated using the CellSearch method in a prospective correlative study in men with mCRPC starting a new systemic therapy. The primary objective was to determine the clinical phenotype of the subset of men with mCRPC who have a poor prognosis and low CTCs. Secondary end points included associations of CTCs with survival and known prognostic biomarkers, before therapy and at progression. Results: At baseline, median CTC count was 16 cells and prostate-specific antigen (PSA) level was 178. ng/ml. At progression, median CTC count was 42, PSA level was 245. ng/ml, levels of lactate dehydrogenase and alkaline phosphatase rose, and level of hemoglobin dropped. The median overall survival for this heavily pretreated population was 11.2 months, and the multivariable hazard ratio for death of men with CTCs < 5 vs.≥5 was 0.43 (95% CI: 0.24-0.77). Median progression-free survival was 4.4 months. CTC enumeration modestly correlated with lactate dehydrogenase and alkaline phosphatase levels but only weakly correlated with PSA and hemoglobin levels. We were unable to iden tify a consistent subgroup of poor prognosis men with a low number of CTCs. Conclusion: CTC enumeration appears to be prognostic in men with mCRPC and describes a phenotype of hematogenous dissemination that cannot be predicted based on standard clinical and laboratory assessments.

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Goodin, M; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Goodin, M, and Armstrong, AJ. "Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer." Urologic Oncology: Seminars and Original Investigations 33.3 (March 1, 2015): 110.e1-110.e9.
Source
scopus
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
33
Issue
3
Publish Date
2015
Start Page
110.e1
End Page
110.e9
DOI
10.1016/j.urolonc.2014.09.002

Burden of disease matters when it comes to systemic therapy for prostate cancer.

Authors
Harrison, MR; Armstrong, AJ
MLA Citation
Harrison, MR, and Armstrong, AJ. "Burden of disease matters when it comes to systemic therapy for prostate cancer." Eur Urol 67.3 (March 2015): 448-450.
PMID
24612662
Source
pubmed
Published In
Eur Urol
Volume
67
Issue
3
Publish Date
2015
Start Page
448
End Page
450
DOI
10.1016/j.eururo.2014.02.032

Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer.

Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain.We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents.AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross-resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents.

Authors
Zhang, T; Zhu, J; George, DJ; Armstrong, AJ
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Armstrong, AJ. "Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer." Expert opinion on pharmacotherapy 16.4 (March 2015): 473-485. (Review)
PMID
25534660
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
16
Issue
4
Publish Date
2015
Start Page
473
End Page
485
DOI
10.1517/14656566.2015.995090

Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer.

The presence of ≥5 circulating tumor cells (CTCs) is prognostic for shorter survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, some men have low CTCs despite widespread disease, suggesting heterogeneity in CTC phenotype or detection. The aim of this study was to evaluate the association of CTC enumeration with clinical disease characteristics and overall survival in men with mCRPC at our institution.CTCs were enumerated using the CellSearch method in a prospective correlative study in men with mCRPC starting a new systemic therapy. The primary objective was to determine the clinical phenotype of the subset of men with mCRPC who have a poor prognosis and low CTCs. Secondary end points included associations of CTCs with survival and known prognostic biomarkers, before therapy and at progression.At baseline, median CTC count was 16 cells and prostate-specific antigen (PSA) level was 178 ng/ml. At progression, median CTC count was 42, PSA level was 245 ng/ml, levels of lactate dehydrogenase and alkaline phosphatase rose, and level of hemoglobin dropped. The median overall survival for this heavily pretreated population was 11.2 months, and the multivariable hazard ratio for death of men with CTCs<5 vs.≥5 was 0.43 (95% CI: 0.24-0.77). Median progression-free survival was 4.4 months. CTC enumeration modestly correlated with lactate dehydrogenase and alkaline phosphatase levels but only weakly correlated with PSA and hemoglobin levels. We were unable to identify a consistent subgroup of poor prognosis men with a low number of CTCs.CTC enumeration appears to be prognostic in men with mCRPC and describes a phenotype of hematogenous dissemination that cannot be predicted based on standard clinical and laboratory assessments.

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Goodin, M; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Goodin, M, and Armstrong, AJ. "Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer." Urologic oncology 33.3 (March 2015): 110.e1-110.e9.
PMID
25595577
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
33
Issue
3
Publish Date
2015
Start Page
110.e1
End Page
110.e9
DOI
10.1016/j.urolonc.2014.09.002

Characteristics of African Americans (AAs) treated with sipuleucel-T (sip-T): Comparison of clinical trial and real-world experience.

Authors
Tutrone, RF; Ahaghotu, C; Armstrong, AJ; Higano, CS; Cooperberg, MR; Belkoff, LH; Olsson, CA; Goel, S; Tyler, RC; LIll, JS; Gray, TE; McCoy, C; Sartor, AO
MLA Citation
Tutrone, RF, Ahaghotu, C, Armstrong, AJ, Higano, CS, Cooperberg, MR, Belkoff, LH, Olsson, CA, Goel, S, Tyler, RC, LIll, JS, Gray, TE, McCoy, C, and Sartor, AO. "Characteristics of African Americans (AAs) treated with sipuleucel-T (sip-T): Comparison of clinical trial and real-world experience." March 2015.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
7_suppl
Publish Date
2015
Start Page
272
End Page
272
DOI
10.1200/jco.2015.33.7_suppl.272

Clinical outcomes and safety in men ≥ 75 and < 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial.

Authors
Graff, JN; Baciarello, G; Armstrong, AJ; Higano, CS; Iversen, P; Forer, D; Mansbach, HH; Phung, D; Tombal, BF; Beer, TM; Sternberg, CN
MLA Citation
Graff, JN, Baciarello, G, Armstrong, AJ, Higano, CS, Iversen, P, Forer, D, Mansbach, HH, Phung, D, Tombal, BF, Beer, TM, and Sternberg, CN. "Clinical outcomes and safety in men ≥ 75 and < 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial." March 2015.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
7_suppl
Publish Date
2015
Start Page
200
End Page
200
DOI
10.1200/jco.2015.33.7_suppl.200

Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal malignancies.

Authors
Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal malignancies." January 20, 2015.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
3_suppl
Publish Date
2015
Start Page
84
End Page
84
DOI
10.1200/jco.2015.33.3_suppl.84

Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity

© 2014 European Association of Urology. Context Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. Objective To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. Evidence acquisition A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. Evidence synthesis The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. Conclusions Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. Patient summary Kidney cancer can be subdivided into related but different cancers that arise from the kidney's tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtype's clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies.

Authors
Shuch, B; Amin, A; Armstrong, AJ; Eble, JN; Ficarra, V; Lopez-Beltran, A; Martignoni, G; Rini, BI; Kutikov, A
MLA Citation
Shuch, B, Amin, A, Armstrong, AJ, Eble, JN, Ficarra, V, Lopez-Beltran, A, Martignoni, G, Rini, BI, and Kutikov, A. "Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity." European Urology 67.1 (January 1, 2015): 85-97.
Source
scopus
Published In
European Urology
Volume
67
Issue
1
Publish Date
2015
Start Page
85
End Page
97
DOI
10.1016/j.eururo.2014.04.029

Prognostic and predictive biomarkers for castration resistant prostate cancer

© Springer Science+Business Media Dordrecht 2015. Despite significant advances in diagnosis and management, prostate cancer is still a leading cause of cancer-related death in men. Castration-resistant prostate cancer (CRPC) is defined by disease progression despite androgen deprivation and castrate levels of testosterone. There have been a rapidly increasing number of new systematic agents which have been approved by the USFDA for men with metastatic CRPC, based on the results of successful phase 3 trials of a diverse range of agents with immunomodulatory, hormonal, bone-targeting, and microtubule-targeting mechanisms of action. Therefore, it is becoming essential to understand the optimal and rational combination and sequences of these treatments in the clinic, as well as to identify patients most likely to benefit from a specific treatment. Minimizing harms and costs of ineffective therapies is an equally important goal. Predictive biomarkers linked to relevant clinical outcomes are thus needed in drug development in CRPC, and there is an increasing need for these biomarkers to guide a clinician’s decision. We discuss in this chapter existing and emerging prognostic and predictive biomarkers in CRPC and future directions of biomarker development in men with CRPC.

Authors
Li, J; Armstrong, AJ
MLA Citation
Li, J, and Armstrong, AJ. "Prognostic and predictive biomarkers for castration resistant prostate cancer." Biomarkers in Disease: Methods, Discoveries and Applications: Biomarkers in Cancer. January 1, 2015. 447-480.
Source
scopus
Publish Date
2015
Start Page
447
End Page
480
DOI
10.1007/978-94-007-7681-4_13

Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity.

Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron.To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes.A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria.The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies.Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space.Kidney cancer can be subdivided into related but different cancers that arise from the kidney's tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtype's clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies.

Authors
Shuch, B; Amin, A; Armstrong, AJ; Eble, JN; Ficarra, V; Lopez-Beltran, A; Martignoni, G; Rini, BI; Kutikov, A
MLA Citation
Shuch, B, Amin, A, Armstrong, AJ, Eble, JN, Ficarra, V, Lopez-Beltran, A, Martignoni, G, Rini, BI, and Kutikov, A. "Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity." European Urology 67.1 (January 2015): 85-97. (Review)
PMID
24857407
Source
epmc
Published In
European Urology
Volume
67
Issue
1
Publish Date
2015
Start Page
85
End Page
97
DOI
10.1016/j.eururo.2014.04.029

Using circulating tumor cells to inform on prostate cancer biology and clinical utility.

Substantial advances in the molecular biology of prostate cancer have led to the approval of multiple new systemic agents to treat men with metastatic castration-resistant prostate cancer (mCRPC). These treatments encompass androgen receptor directed therapies, immunotherapies, bone targeting radiopharmaceuticals and cytotoxic chemotherapies. There is, however, great heterogeneity in the degree of patient benefit with these agents, thus fueling the need to develop predictive biomarkers that are able to rationally guide therapy. Circulating tumor cells (CTCs) have the potential to provide an assessment of tumor-specific biomarkers through a non-invasive, repeatable "liquid biopsy" of a patient's cancer at a given point in time. CTCs have been extensively studied in men with mCRPC, where CTC enumeration using the Cellsearch® method has been validated and FDA approved to be used in conjunction with other clinical parameters as a prognostic biomarker in metastatic prostate cancer. In addition to enumeration, more sophisticated molecular profiling of CTCs is now feasible and may provide more clinical utility as it may reflect tumor evolution within an individual particularly under the pressure of systemic therapies. Here, we review technologies used to detect and characterize CTCs, and the potential biological and clinical utility of CTC molecular profiling in men with metastatic prostate cancer.

Authors
Li, J; Gregory, SG; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Li, J, Gregory, SG, Garcia-Blanco, MA, and Armstrong, AJ. "Using circulating tumor cells to inform on prostate cancer biology and clinical utility." Critical reviews in clinical laboratory sciences 52.4 (January 2015): 191-210. (Review)
PMID
26079252
Source
epmc
Published In
Critical Reviews in Clinical Laboratory Sciences
Volume
52
Issue
4
Publish Date
2015
Start Page
191
End Page
210
DOI
10.3109/10408363.2015.1023430

Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?

OBJECTIVES: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. METHODS: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prostate cancer multidisciplinary clinic (n = 194) and standard urology clinic (n = 741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and χ(2) -tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. RESULTS: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P = 0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P = 0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P = 0.249) or pathological variables (hazard ratio 0.75, P = 0.349). CONCLUSIONS: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients.

Authors
Stewart, SB; Moul, JW; Polascik, TJ; Koontz, BF; Robertson, CN; Freedland, SJ; George, DJ; Lee, WR; Armstrong, AJ; Bañez, LL
MLA Citation
Stewart, SB, Moul, JW, Polascik, TJ, Koontz, BF, Robertson, CN, Freedland, SJ, George, DJ, Lee, WR, Armstrong, AJ, and Bañez, LL. "Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?." International Journal of Urology : Official Journal of the Japanese Urological Association 21.12 (December 2014): 1215-1219.
PMID
25041422
Source
epmc
Published In
International Journal of Urology : Official Journal of the Japanese Urological Association
Volume
21
Issue
12
Publish Date
2014
Start Page
1215
End Page
1219
DOI
10.1111/iju.12561

Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer.

To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

Authors
Sonpavde, G; Pond, GR; Armstrong, AJ; Galsky, MD; Leopold, L; Wood, BA; Wang, S-L; Paolini, J; Chen, I; Chow-Maneval, E; Mooney, DJ; Lechuga, M; Smith, MR; Michaelson, MD
MLA Citation
Sonpavde, G, Pond, GR, Armstrong, AJ, Galsky, MD, Leopold, L, Wood, BA, Wang, S-L, Paolini, J, Chen, I, Chow-Maneval, E, Mooney, DJ, Lechuga, M, Smith, MR, and Michaelson, MD. "Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer." BJU international 114.6b (December 2014): E25-E31.
PMID
24298897
Source
epmc
Published In
Bju International
Volume
114
Issue
6b
Publish Date
2014
Start Page
E25
End Page
E31
DOI
10.1111/bju.12589

Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC).

Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC).Bone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIbone(BSI), an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time.Of 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42, P = 0.013) and multivariate (HR = 1.64, P<0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling, P<0.001) and OS (HR = 1.58, P = 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression.BSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted.

Authors
Armstrong, AJ; Kaboteh, R; Carducci, MA; Damber, J-E; Stadler, WM; Hansen, M; Edenbrandt, L; Forsberg, G; Nordle, Ö; Pili, R; Morris, MJ
MLA Citation
Armstrong, AJ, Kaboteh, R, Carducci, MA, Damber, J-E, Stadler, WM, Hansen, M, Edenbrandt, L, Forsberg, G, Nordle, Ö, Pili, R, and Morris, MJ. "Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)." Urologic oncology 32.8 (November 2014): 1308-1316.
PMID
25240761
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
32
Issue
8
Publish Date
2014
Start Page
1308
End Page
1316
DOI
10.1016/j.urolonc.2014.08.006

Abstract SS02-02: A long walk from FGFR2 alternative splicing to cancer progression

Authors
Somarelli, JA; Somarelli, JA; Schaeffer, D; Schaeffer, D; Marengo, MS; Marengo, MS; Bepler, T; Bepler, T; Rouse, D; Buckley, AF; Epstein, JI; Armstrong, AJ; Garcia-Blanco, MA; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Somarelli, JA, Schaeffer, D, Schaeffer, D, Marengo, MS, Marengo, MS, Bepler, T, Bepler, T, Rouse, D, Buckley, AF, Epstein, JI, Armstrong, AJ, Garcia-Blanco, MA, and Garcia-Blanco, MA. "Abstract SS02-02: A long walk from FGFR2 alternative splicing to cancer progression." Cancer Epidemiology Biomarkers & Prevention 23.11 Supplement (November 2014): SS02-02-SS02-02.
Source
crossref
Published In
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
Volume
23
Issue
11 Supplement
Publish Date
2014
Start Page
SS02-02
End Page
SS02-02
DOI
10.1158/1538-7755.DISP13-SS02-02

In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? No, not yet

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? No, not yet." Oncology (Williston Park, N.Y.) 28.10 (October 1, 2014): 883-.
Source
scopus
Published In
Oncology (Williston Park, N.Y.)
Volume
28
Issue
10
Publish Date
2014
Start Page
883

Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer.

We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups.Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715.High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.

Authors
Sonpavde, G; Pond, GR; Armstrong, AJ; Clarke, SJ; Vardy, JL; Templeton, AJ; Wang, S-L; Paolini, J; Chen, I; Chow-Maneval, E; Lechuga, M; Smith, MR; Michaelson, MD
MLA Citation
Sonpavde, G, Pond, GR, Armstrong, AJ, Clarke, SJ, Vardy, JL, Templeton, AJ, Wang, S-L, Paolini, J, Chen, I, Chow-Maneval, E, Lechuga, M, Smith, MR, and Michaelson, MD. "Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer." Clinical Genitourinary Cancer 12.5 (October 2014): 317-324.
PMID
24806399
Source
epmc
Published In
Clinical Genitourinary Cancer
Volume
12
Issue
5
Publish Date
2014
Start Page
317
End Page
324
DOI
10.1016/j.clgc.2014.03.005

In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? No, not yet.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "In hormone-naive metastatic prostate cancer, should all patients now receive docetaxel? No, not yet." Oncology (Williston Park, N.Y.) 28.10 (October 2014): 881-883.
PMID
25323615
Source
epmc
Published In
Oncology (Williston Park, N.Y.)
Volume
28
Issue
10
Publish Date
2014
Start Page
881
End Page
883

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance.

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches.

Authors
Bitting, RL; Schaeffer, D; Somarelli, JA; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Bitting, RL, Schaeffer, D, Somarelli, JA, Garcia-Blanco, MA, and Armstrong, AJ. "The role of epithelial plasticity in prostate cancer dissemination and treatment resistance." Cancer Metastasis Reviews 33.2-3 (September 2014): 441-468. (Review)
PMID
24414193
Source
epmc
Published In
Cancer Metastasis Reviews
Volume
33
Issue
2-3
Publish Date
2014
Start Page
441
End Page
468
DOI
10.1007/s10555-013-9483-z

Impact of Prior Radiation Treatment on Sipuleucel-T Product Parameters in PROCEED Patients

Authors
Furay, A; Nordquist, L; Dakhil, S; Green, N; Heath, E; Tutrone, R; Vogelzang, N; Armstrong, A; Cooperberg, M; Tyler, R; Whitmore, J; Higano, C
MLA Citation
Furay, A, Nordquist, L, Dakhil, S, Green, N, Heath, E, Tutrone, R, Vogelzang, N, Armstrong, A, Cooperberg, M, Tyler, R, Whitmore, J, and Higano, C. "Impact of Prior Radiation Treatment on Sipuleucel-T Product Parameters in PROCEED Patients." September 2014.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
90
Issue
1
Publish Date
2014
Start Page
S407
End Page
S408
DOI
10.1016/j.ijrobp.2014.05.1296

1072PEXPERIENCE OF PATIENTS TREATED WITH SIPULEUCEL-T IN AN ACADEMIC SETTING.

Authors
Bhavsar, NA; Harrison, MR; Howie, LJ; Armstrong, AJ; Davis, K; Chen, Q; Pupa, MR; Abernethy, A; George, DJ; Hirsch, BR
MLA Citation
Bhavsar, NA, Harrison, MR, Howie, LJ, Armstrong, AJ, Davis, K, Chen, Q, Pupa, MR, Abernethy, A, George, DJ, and Hirsch, BR. "1072PEXPERIENCE OF PATIENTS TREATED WITH SIPULEUCEL-T IN AN ACADEMIC SETTING." September 2014.
PMID
28171524
Source
epmc
Published In
Annals of Oncology
Volume
25
Issue
suppl_4
Publish Date
2014
Start Page
iv369
End Page
iv370

795PA PROGNOSTIC MODEL FOR PREDICTING RADIOGRAPHIC PROGRESSION- FREE SURVIVAL (RPFS) IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER MEN TREATED WITH SECOND-LINE CHEMOTHERAPY.

Authors
Halabi, S; Zhou, H; Small, EJ; Solomon, NC; Armstrong, AJ; Shen, L; Oudard, S; Sartor, O; de Bono, JS
MLA Citation
Halabi, S, Zhou, H, Small, EJ, Solomon, NC, Armstrong, AJ, Shen, L, Oudard, S, Sartor, O, and de Bono, JS. "795PA PROGNOSTIC MODEL FOR PREDICTING RADIOGRAPHIC PROGRESSION- FREE SURVIVAL (RPFS) IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER MEN TREATED WITH SECOND-LINE CHEMOTHERAPY." Annals of oncology : official journal of the European Society for Medical Oncology 25.suppl_4 (September 2014): iv276-.
PMID
28174822
Source
epmc
Published In
Annals of Oncology
Volume
25
Issue
suppl_4
Publish Date
2014
Start Page
iv276

A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.

Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical genitourinary cancer 12.4 (August 2014): 241-250.
PMID
24685058
Source
epmc
Published In
Clinical Genitourinary Cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.

As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

Authors
Ware, KE; Garcia-Blanco, MA; Armstrong, AJ; Dehm, SM
MLA Citation
Ware, KE, Garcia-Blanco, MA, Armstrong, AJ, and Dehm, SM. "Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer." Endocrine Related Cancer 21.4 (August 2014): T87-T103. (Review)
PMID
24859991
Source
epmc
Published In
Endocrine Related Cancer
Volume
21
Issue
4
Publish Date
2014
Start Page
T87
End Page
T103
DOI
10.1530/ERC-13-0470

Enzalutamide in metastatic prostate cancer before chemotherapy.

Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Authors
Beer, TM; Armstrong, AJ; Rathkopf, DE; Loriot, Y; Sternberg, CN; Higano, CS; Iversen, P; Bhattacharya, S; Carles, J; Chowdhury, S; Davis, ID; de Bono, JS; Evans, CP; Fizazi, K; Joshua, AM; Kim, C-S; Kimura, G; Mainwaring, P; Mansbach, H; Miller, K; Noonberg, SB; Perabo, F; Phung, D; Saad, F; Scher, HI; Taplin, M-E; Venner, PM; Tombal, B; PREVAIL Investigators,
MLA Citation
Beer, TM, Armstrong, AJ, Rathkopf, DE, Loriot, Y, Sternberg, CN, Higano, CS, Iversen, P, Bhattacharya, S, Carles, J, Chowdhury, S, Davis, ID, de Bono, JS, Evans, CP, Fizazi, K, Joshua, AM, Kim, C-S, Kimura, G, Mainwaring, P, Mansbach, H, Miller, K, Noonberg, SB, Perabo, F, Phung, D, Saad, F, Scher, HI, Taplin, M-E, Venner, PM, Tombal, B, and PREVAIL Investigators, . "Enzalutamide in metastatic prostate cancer before chemotherapy." The New England Journal of Medicine 371.5 (July 2014): 424-433.
PMID
24881730
Source
epmc
Published In
The New England Journal of Medicine
Volume
371
Issue
5
Publish Date
2014
Start Page
424
End Page
433
DOI
10.1056/NEJMoa1405095

Primary, secondary, and quality-of-life endpoint results from PREVAIL, a phase 3 study of enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).

Authors
Armstrong, AJ; Tombal, B; Sternberg, CN; Higano, CS; Rathkopf, DE; Loriot, Y; Saad, F; Joshua, AM; De Bono, JS; Venner, PM; Caries, J; Mainwaring, PN; Evans, CP; Noonberg, SB; Mansbach, HH; Bhattacharya, S; Perabo, F; Phung, D; Beer, TM
MLA Citation
Armstrong, AJ, Tombal, B, Sternberg, CN, Higano, CS, Rathkopf, DE, Loriot, Y, Saad, F, Joshua, AM, De Bono, JS, Venner, PM, Caries, J, Mainwaring, PN, Evans, CP, Noonberg, SB, Mansbach, HH, Bhattacharya, S, Perabo, F, Phung, D, and Beer, TM. "Primary, secondary, and quality-of-life endpoint results from PREVAIL, a phase 3 study of enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Sensitivity analyses for radiographic progression-free survival (rPFS): Results from the phase 3 PREVAIL trial comparing enzalutamide to placebo.

Authors
Morris, MJ; Loriot, Y; Beer, TM; Higano, CS; Armstrong, AJ; Sternberg, CN; De Bono, JS; Tombal, BF; Noonberg, SB; Mansbach, HH; Bhattacharya, S; Perabo, F; Phung, D; Rathkopf, DE
MLA Citation
Morris, MJ, Loriot, Y, Beer, TM, Higano, CS, Armstrong, AJ, Sternberg, CN, De Bono, JS, Tombal, BF, Noonberg, SB, Mansbach, HH, Bhattacharya, S, Perabo, F, Phung, D, and Rathkopf, DE. "Sensitivity analyses for radiographic progression-free survival (rPFS): Results from the phase 3 PREVAIL trial comparing enzalutamide to placebo." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC)

Authors
Zhang, T; Dhawan, MS; Healy, P; George, DJ; Olden, J; Chin, B; Armstrong, AJ
MLA Citation
Zhang, T, Dhawan, MS, Healy, P, George, DJ, Olden, J, Chin, B, and Armstrong, AJ. "Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

The site of visceral metastases (mets) to predict overall survival (OS) in castration-resistant prostate cancer (CRPC) patients (pts): A meta-analysis of five phase III trials

Authors
Halabi, S; Kelly, WK; Zhou, H; Armstrong, AJ; Quinn, D; Fizazi, K; Solomon, NC; Tannock, I; Petrylak, DP; Morris, MJ; Small, EJ
MLA Citation
Halabi, S, Kelly, WK, Zhou, H, Armstrong, AJ, Quinn, D, Fizazi, K, Solomon, NC, Tannock, I, Petrylak, DP, Morris, MJ, and Small, EJ. "The site of visceral metastases (mets) to predict overall survival (OS) in castration-resistant prostate cancer (CRPC) patients (pts): A meta-analysis of five phase III trials." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy

Authors
Li, J; Beaver, J; Bitting, RL; Gregory, S; Armstrong, AJ
MLA Citation
Li, J, Beaver, J, Bitting, RL, Gregory, S, and Armstrong, AJ. "Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

A randomized, open label, multicenter, phase 3, 2-arm study of androgen deprivation with leuprolide (L), +/- docetaxel (D) for clinically asymptomatic prostate cancer (PC) subjects with a rising PSA following definitive local therapy: Safety results.

Authors
Morris, MJ; Gleave, ME; Armstrong, AJ; Carducci, MA; Saad, F; Lacuna, KP; Scher, HI
MLA Citation
Morris, MJ, Gleave, ME, Armstrong, AJ, Carducci, MA, Saad, F, Lacuna, KP, and Scher, HI. "A randomized, open label, multicenter, phase 3, 2-arm study of androgen deprivation with leuprolide (L), +/- docetaxel (D) for clinically asymptomatic prostate cancer (PC) subjects with a rising PSA following definitive local therapy: Safety results." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer.

This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial.Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored.Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03).Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

Authors
Younis, IR; George, DJ; McManus, TJ; Hurwitz, H; Creel, P; Armstrong, AJ; Yu, JJ; Bacon, K; Hobbs, G; Peer, CJ; Petros, WP
MLA Citation
Younis, IR, George, DJ, McManus, TJ, Hurwitz, H, Creel, P, Armstrong, AJ, Yu, JJ, Bacon, K, Hobbs, G, Peer, CJ, and Petros, WP. "Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer." Cancer chemotherapy and pharmacology 73.5 (May 2014): 991-997.
PMID
24619498
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
73
Issue
5
Publish Date
2014
Start Page
991
End Page
997
DOI
10.1007/s00280-014-2432-x

Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes.

Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.

Authors
Aggarwal, R; Zhang, T; Small, EJ; Armstrong, AJ
MLA Citation
Aggarwal, R, Zhang, T, Small, EJ, and Armstrong, AJ. "Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes." Journal of the National Comprehensive Cancer Network : Jnccn 12.5 (May 2014): 719-726. (Review)
PMID
24812138
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
12
Issue
5
Publish Date
2014
Start Page
719
End Page
726
DOI
10.6004/jnccn.2014.0073

Prostate cancer, version 2.2014.

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

Authors
Mohler, JL; Kantoff, PW; Armstrong, AJ; Bahnson, RR; Cohen, M; D'Amico, AV; Eastham, JA; Enke, CA; Farrington, TA; Higano, CS; Horwitz, EM; Kane, CJ; Kawachi, MH; Kuettel, M; Kuzel, TM; Lee, RJ; Malcolm, AW; Miller, D; Plimack, ER; Pow-Sang, JM; Raben, D; Richey, S; Roach, M; Rohren, E; Rosenfeld, S; Schaeffer, E; Small, EJ; Sonpavde, G; Srinivas, S; Stein, C; Strope, SA; Tward, J; Shead, DA; Ho, M; National Comprehensive Cancer Network,
MLA Citation
Mohler, JL, Kantoff, PW, Armstrong, AJ, Bahnson, RR, Cohen, M, D'Amico, AV, Eastham, JA, Enke, CA, Farrington, TA, Higano, CS, Horwitz, EM, Kane, CJ, Kawachi, MH, Kuettel, M, Kuzel, TM, Lee, RJ, Malcolm, AW, Miller, D, Plimack, ER, Pow-Sang, JM, Raben, D, Richey, S, Roach, M, Rohren, E, Rosenfeld, S, Schaeffer, E, Small, EJ, Sonpavde, G, Srinivas, S, Stein, C, Strope, SA, Tward, J, Shead, DA, Ho, M, and National Comprehensive Cancer Network, . "Prostate cancer, version 2.2014." Journal of the National Comprehensive Cancer Network : JNCCN 12.5 (May 2014): 686-718.
PMID
24812137
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
12
Issue
5
Publish Date
2014
Start Page
686
End Page
718
DOI
10.6004/jnccn.2014.0072

New treatments for men with castration-resistant prostate cancer: Can we move from small steps to giant leaps?

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "New treatments for men with castration-resistant prostate cancer: Can we move from small steps to giant leaps?." European Urology 65.2 (February 1, 2014): 300-302.
Source
scopus
Published In
European Urology
Volume
65
Issue
2
Publish Date
2014
Start Page
300
End Page
302
DOI
10.1016/j.eururo.2013.08.059

Biomarkers in castration-resistant prostate cancer

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Biomarkers in castration-resistant prostate cancer." Clinical Advances in Hematology and Oncology 12.2 (February 1, 2014): 115-118.
Source
scopus
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
12
Issue
2
Publish Date
2014
Start Page
115
End Page
118

Biomarkers in castration-resistant prostate cancer.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Biomarkers in castration-resistant prostate cancer." Clinical advances in hematology & oncology : H&O 12.2 (February 2014): 115-118.
PMID
24892256
Source
epmc
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
12
Issue
2
Publish Date
2014
Start Page
115
End Page
118

Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment.

Authors
Armstrong, AJ; Bitting, RL; Kemeny, G; George, DJ
MLA Citation
Armstrong, AJ, Bitting, RL, Kemeny, G, and George, DJ. "Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
178
End Page
178
DOI
10.1200/jco.2014.32.4_suppl.178

Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.

Authors
Beer, TM; Armstrong, AJ; Sternberg, CN; Higano, CS; Iversen, P; Loriot, Y; Rathkopf, DE; Bhattacharya, S; Carles, J; De Bono, JS; Evans, CP; Joshua, AM; Kim, C-S; Kimura, G; Mainwaring, PN; Mansbach, HH; Miller, K; Noonberg, SB; Venner, PM; Tombal, B
MLA Citation
Beer, TM, Armstrong, AJ, Sternberg, CN, Higano, CS, Iversen, P, Loriot, Y, Rathkopf, DE, Bhattacharya, S, Carles, J, De Bono, JS, Evans, CP, Joshua, AM, Kim, C-S, Kimura, G, Mainwaring, PN, Mansbach, HH, Miller, K, Noonberg, SB, Venner, PM, and Tombal, B. "Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
LBA1
End Page
LBA1
DOI
10.1200/jco.2014.32.4_suppl.lba1

Impact of prior radiation treatment (tx) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).

Authors
Finkelstein, SE; Nordquist, LT; Dakhil, SR; Green, NB; Heath, EI; Tutrone, R; Vogelzang, NJ; Armstrong, AJ; Cooperberg, MR; Tyler, RC; Sims, RB; Whitmore, JB; Higano, CS
MLA Citation
Finkelstein, SE, Nordquist, LT, Dakhil, SR, Green, NB, Heath, EI, Tutrone, R, Vogelzang, NJ, Armstrong, AJ, Cooperberg, MR, Tyler, RC, Sims, RB, Whitmore, JB, and Higano, CS. "Impact of prior radiation treatment (tx) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts)." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
183
End Page
183
DOI
10.1200/jco.2014.32.4_suppl.183

Sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) patients ≥80 years-old: Data from PROCEED.

Authors
Nabhan, C; Sartor, AO; Cooperberg, MR; Armstrong, AJ; Vacirca, JL; Concepcion, RS; Berry, WR; Dhawan, M; Tutrone, R; Sandler, A; McCoy, C; Whitmore, JB; Tyler, RC; Higano, CS
MLA Citation
Nabhan, C, Sartor, AO, Cooperberg, MR, Armstrong, AJ, Vacirca, JL, Concepcion, RS, Berry, WR, Dhawan, M, Tutrone, R, Sandler, A, McCoy, C, Whitmore, JB, Tyler, RC, and Higano, CS. "Sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) patients ≥80 years-old: Data from PROCEED." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
64
End Page
64
DOI
10.1200/jco.2014.32.4_suppl.64

Effect of prior abiraterone (ABI) or enzalutamide (ENZ) on sipuleucel-T (sip-T) manufacture in PROCEED patients (pts).

Authors
Vogelzang, NJ; Vacirca, JL; Kantoff, PW; Scholz, MC; Dakhil, SR; Nordquist, LT; Higano, CS; Sartor, AO; Cooperberg, MR; Sandler, A; McCoy, C; Whitmore, JB; Tyler, RC; Armstrong, AJ
MLA Citation
Vogelzang, NJ, Vacirca, JL, Kantoff, PW, Scholz, MC, Dakhil, SR, Nordquist, LT, Higano, CS, Sartor, AO, Cooperberg, MR, Sandler, A, McCoy, C, Whitmore, JB, Tyler, RC, and Armstrong, AJ. "Effect of prior abiraterone (ABI) or enzalutamide (ENZ) on sipuleucel-T (sip-T) manufacture in PROCEED patients (pts)." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
185
End Page
185
DOI
10.1200/jco.2014.32.4_suppl.185

Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy.

Authors
Armstrong, AJ; Li, J; Beaver, J; Bitting, RL; Gregory, S
MLA Citation
Armstrong, AJ, Li, J, Beaver, J, Bitting, RL, and Gregory, S. "Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy." February 2014.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
4_suppl
Publish Date
2014
Start Page
65
End Page
65
DOI
10.1200/jco.2014.32.4_suppl.65

New treatments for men with castration-resistant prostate cancer: can we move from small steps to giant leaps?

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "New treatments for men with castration-resistant prostate cancer: can we move from small steps to giant leaps?." Eur Urol 65.2 (February 2014): 300-302.
PMID
24054873
Source
pubmed
Published In
Eur Urol
Volume
65
Issue
2
Publish Date
2014
Start Page
300
End Page
302
DOI
10.1016/j.eururo.2013.08.059

The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer

The presence of visceral metastases is adversely prognostic in men with metastatic castration-resistant prostate cancer (mCRPC), but the prognostic impact of the site of visceral metastasis is unclear. Men with mCRPC in the TAX 327 phase 3 trial receiving docetaxel or mitoxantrone every 3 wk or weekly docetaxel, each with prednisone, were analyzed retrospectively to study the impact of the site of visceral metastasis on overall survival (OS). Patients were assessed for OS by site of metastases: liver with or without other sites, lung with or without bone or lymph nodes, bone plus lymph nodes, bone only, and lymph nodes only. Cox proportional hazards regression, adjusted for treatment and stratification factors, was performed. Men with liver metastases with or without other metastases had shorter median OS (10.0 mo; 95% confidence interval [CI], 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 mo; 95% CI, 11.5-22.4). Men with lymph node-only disease had the best median OS (26.7 mo; 95% CI, 22.3-34.2), followed by men with bone-only metastases (median OS: 19.0 mo; 95% CI, 18.2-20.7) and bone-plus-node disease (median OS: 15.7 mo; 95% CI, 14.4-17.2). Thus, pattern of spread including site of visceral metastasis confers a differential prognostic impact. These data require validation and may inform trial design and therapy. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Authors
Pond, GR; Sonpavde, G; De Wit, R; Eisenberger, MA; Tannock, IF; Armstrong, AJ
MLA Citation
Pond, GR, Sonpavde, G, De Wit, R, Eisenberger, MA, Tannock, IF, and Armstrong, AJ. "The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer." European Urology 65.1 (January 1, 2014): 3-6.
Source
scopus
Published In
European Urology
Volume
65
Issue
1
Publish Date
2014
Start Page
3
End Page
6
DOI
10.1016/j.eururo.2013.09.024

Prostate Cancer,,Version 2.2014 Clinical Practice Guidelines in Oncology

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website. © National Comprehensive Cancer Network, Inc. 2014, All rights reserved.

Authors
Mohler, JL; Kantoff, PW; Armstrong, AJ; Bahnson, RR; Cohen, M; D'Amico, AV; Eastham, JA; Enke, CA; Farrington, TA; Higano, CS; Horwitz, EM; Kane, CJ; Kawachi, MH; Kuettel, M; Kuzel, TM; Lee, RJ; Malcolm, AW; Miller, D; Plimack, ER; Pow-Sang, JM; Raben, D; Richey, S; Roach, M; Rohren, E; Rosenfeld, S; Schaeffer, E; Small, EJ; Sonpavde, G; Srinivas, S; Stein, C; Strope, SA; Tward, J; Shead, DA; Ho, M
MLA Citation
Mohler, JL, Kantoff, PW, Armstrong, AJ, Bahnson, RR, Cohen, M, D'Amico, AV, Eastham, JA, Enke, CA, Farrington, TA, Higano, CS, Horwitz, EM, Kane, CJ, Kawachi, MH, Kuettel, M, Kuzel, TM, Lee, RJ, Malcolm, AW, Miller, D, Plimack, ER, Pow-Sang, JM, Raben, D, Richey, S, Roach, M, Rohren, E, Rosenfeld, S, Schaeffer, E, Small, EJ, Sonpavde, G, Srinivas, S, Stein, C, Strope, SA, Tward, J, Shead, DA, and Ho, M. "Prostate Cancer,,Version 2.2014 Clinical Practice Guidelines in Oncology." Jnccn Journal of the National Comprehensive Cancer Network 12.5 (January 1, 2014): 686-718. (Review)
Source
scopus
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
12
Issue
5
Publish Date
2014
Start Page
686
End Page
718
DOI
10.6004/jnccn.2014.0072

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

Purpose: This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. Methods: Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m2) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. Results: Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). Conclusion: Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration. © 2014 Springer-Verlag.

Authors
Younis, IR; George, DJ; McManus, TJ; Hurwitz, H; Creel, P; Armstrong, AJ; Yu, JJ; Bacon, K; Hobbs, G; Peer, CJ; Petros, WP
MLA Citation
Younis, IR, George, DJ, McManus, TJ, Hurwitz, H, Creel, P, Armstrong, AJ, Yu, JJ, Bacon, K, Hobbs, G, Peer, CJ, and Petros, WP. "Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer." Cancer Chemotherapy and Pharmacology 73.5 (January 1, 2014): 991-997.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
73
Issue
5
Publish Date
2014
Start Page
991
End Page
997
DOI
10.1007/s00280-014-2432-x

A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma

Background Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). Patients and Methods A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. Results We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability ( > 1 year) was demonstrated in 19% of patients. Conclusion Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. © 2014 Elsevier Inc. All rights reserved.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical Genitourinary Cancer 12.4 (January 1, 2014): 241-250.
Source
scopus
Published In
Clinical Genitourinary Cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches. © 2014 Springer Science+Business Media.

Authors
Bitting, RL; Schaeffer, D; Somarelli, JA; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Bitting, RL, Schaeffer, D, Somarelli, JA, Garcia-Blanco, MA, and Armstrong, AJ. "The role of epithelial plasticity in prostate cancer dissemination and treatment resistance." Cancer and Metastasis Reviews 33.2-3 (January 1, 2014): 441-468.
Source
scopus
Published In
Cancer Metastasis Reviews
Volume
33
Issue
2-3
Publish Date
2014
Start Page
441
End Page
468
DOI
10.1007/s10555-013-9483-z

Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer

© 2014 Elsevier Inc. All rights reserved. This retrospective analysis of a phase III trial comparing prednisone combined with sunitinib or placebo following docetaxel for metastatic castration resistant prostate cancer demonstrated the prognostic impact of peripheral blood neutrophil-lymphocyte ratio (NLR) independent of known prognostic factors. NLR warrants external validation, given its ready and inexpensive availability, and the potential role of the host immune in modulating tumor biology. Background: We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. Methods: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. Results: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), lognumber of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. Conclusion: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.

Authors
Sonpavde, G; Pond, GR; Armstrong, AJ; Clarke, SJ; Vardy, JL; Templeton, AJ; Wang, SL; Paolini, J; Chen, I; Chow-Maneval, E; Lechuga, M; Smith, MR; Dror Michaelson, M
MLA Citation
Sonpavde, G, Pond, GR, Armstrong, AJ, Clarke, SJ, Vardy, JL, Templeton, AJ, Wang, SL, Paolini, J, Chen, I, Chow-Maneval, E, Lechuga, M, Smith, MR, and Dror Michaelson, M. "Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer." Clinical Genitourinary Cancer 12.5 (January 1, 2014): 317-324.
Source
scopus
Published In
Clinical Genitourinary Cancer
Volume
12
Issue
5
Publish Date
2014
Start Page
317
End Page
324
DOI
10.1016/j.clgc.2014.03.005

Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?

© 2014 The Japanese Urological Association. Objectives: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. Methods: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prost ate cancer multidisciplinary clinic (n=194) and standard urology clinic (n=741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and χ 2 -tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. Results: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P=0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P=0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P=0.249) or pathological variables (hazard ratio 0.75, P=0.349). Conclusions: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients.

Authors
Stewart, SB; Moul, JW; Polascik, TJ; Koontz, BF; Robertson, CN; Freedland, SJ; George, DJ; Lee, WR; Armstrong, AJ; Bañez, LL
MLA Citation
Stewart, SB, Moul, JW, Polascik, TJ, Koontz, BF, Robertson, CN, Freedland, SJ, George, DJ, Lee, WR, Armstrong, AJ, and Bañez, LL. "Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?." International Journal of Urology 21.12 (January 1, 2014): 1215-1219.
Source
scopus
Published In
International Journal of Urology : Official Journal of the Japanese Urological Association
Volume
21
Issue
12
Publish Date
2014
Start Page
1215
End Page
1219
DOI
10.1111/iju.12561

Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)1A.J.A. and R.K. contributed equally to this work

© 2014 Elsevier Inc. Introduction: Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC). Methods: Bone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIbone BSI , an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time. Results: Of 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42, P = 0.013) and multivariate (HR = 1.64, P < 0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling, P < 0.001) and OS (HR = 1.58, P = 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression. Conclusions: BSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted.

Authors
Armstrong, AJ; Kaboteh, R; Carducci, MA; Damber, JE; Stadler, WM; Hansen, M; Edenbrandt, L; Forsberg, G; Nordle, Ö; Pili, R; Morris, MJ
MLA Citation
Armstrong, AJ, Kaboteh, R, Carducci, MA, Damber, JE, Stadler, WM, Hansen, M, Edenbrandt, L, Forsberg, G, Nordle, Ö, Pili, R, and Morris, MJ. "Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)1A.J.A. and R.K. contributed equally to this work." Urologic Oncology: Seminars and Original Investigations 32.8 (January 1, 2014): 1308-1316.
Source
scopus
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
32
Issue
8
Publish Date
2014
Start Page
1308
End Page
1316
DOI
10.1016/j.urolonc.2014.08.006

The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer.

The presence of visceral metastases is adversely prognostic in men with metastatic castration-resistant prostate cancer (mCRPC), but the prognostic impact of the site of visceral metastasis is unclear. Men with mCRPC in the TAX 327 phase 3 trial receiving docetaxel or mitoxantrone every 3 wk or weekly docetaxel, each with prednisone, were analyzed retrospectively to study the impact of the site of visceral metastasis on overall survival (OS). Patients were assessed for OS by site of metastases: liver with or without other sites, lung with or without bone or lymph nodes, bone plus lymph nodes, bone only, and lymph nodes only. Cox proportional hazards regression, adjusted for treatment and stratification factors, was performed. Men with liver metastases with or without other metastases had shorter median OS (10.0 mo; 95% confidence interval [CI], 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 mo; 95% CI, 11.5-22.4). Men with lymph node-only disease had the best median OS (26.7 mo; 95% CI, 22.3-34.2), followed by men with bone-only metastases (median OS: 19.0 mo; 95% CI, 18.2-20.7) and bone-plus-node disease (median OS: 15.7 mo; 95% CI, 14.4-17.2). Thus, pattern of spread including site of visceral metastasis confers a differential prognostic impact. These data require validation and may inform trial design and therapy.

Authors
Pond, GR; Sonpavde, G; de Wit, R; Eisenberger, MA; Tannock, IF; Armstrong, AJ
MLA Citation
Pond, GR, Sonpavde, G, de Wit, R, Eisenberger, MA, Tannock, IF, and Armstrong, AJ. "The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer." European Urology 65.1 (January 2014): 3-6.
PMID
24120464
Source
epmc
Published In
European Urology
Volume
65
Issue
1
Publish Date
2014
Start Page
3
End Page
6
DOI
10.1016/j.eururo.2013.09.024

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer

Background Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown. Methods We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Conclusion Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. © 2013 Elsevier Inc. All rights reserved.

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, M; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, M, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Clinical Genitourinary Cancer 11.4 (December 1, 2013): 397-406.
Source
scopus
Published In
Clinical Genitourinary Cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
397
End Page
406
DOI
10.1016/j.clgc.2013.05.007

Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer

Background:Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer (PCa) cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.Methods:We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating 'response' (that is, ≥10% decrease in peripheral blood mononuclear cell (PBMC) global 5-methyl cytosine (5 me C) content) was observed in < 3 patients in cohort 1. Cohorts 1 and 2 received disulfiram 250 mg and 500 mg daily, respectively. The primary end point was the proportion of subjects with a demethylation response. Secondary end points included the rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.Results:Changes in global 5 me C content were observed in two of nine patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only five subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events (three per cohort). Three of the responders displayed pretreatment instability in their 5 me C content.Conclusions:A minority of patients had transient global PBMC demethylation changes. Instability in 5 me C may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Schweizer, MT; Lin, J; Blackford, A; Bardia, A; King, S; Armstrong, AJ; Rudek, MA; Yegnasubramanian, S; Carducci, MA
MLA Citation
Schweizer, MT, Lin, J, Blackford, A, Bardia, A, King, S, Armstrong, AJ, Rudek, MA, Yegnasubramanian, S, and Carducci, MA. "Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer." Prostate Cancer and Prostatic Diseases 16.4 (December 1, 2013): 357-361.
Source
scopus
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
357
End Page
361
DOI
10.1038/pcan.2013.28

Development of a method to isolate circulating tumor cells using mesenchymal-based capture

Epithelial tumor cells can become mesenchymal cells and vice versa via phenotypic transitions, a process known as epithelial plasticity. We postulate that during the process of metastasis, circulating tumor cells (CTCs) lose their epithelial phenotype and acquire a mesenchymal phenotype that may not be sufficiently captured by existing epithelial-based CTC technologies. We report here on the development of a novel CTC capture method, based on the biology of epithelial plasticity, which isolates cells based on OB-cadherin cell surface expression. Using this mesenchymal-based assay, OB-cadherin cellular events are detectable in men with metastatic prostate cancer and are less common in healthy volunteers. This method may complement existing epithelial-based methods and may be particularly useful in patients with bone metastases. © 2013 Elsevier Inc.

Authors
Bitting, RL; Boominathan, R; Rao, C; Kemeny, G; Foulk, B; Garcia-Blanco, MA; Connelly, M; Armstrong, AJ
MLA Citation
Bitting, RL, Boominathan, R, Rao, C, Kemeny, G, Foulk, B, Garcia-Blanco, MA, Connelly, M, and Armstrong, AJ. "Development of a method to isolate circulating tumor cells using mesenchymal-based capture." Methods 64.2 (December 1, 2013): 129-136.
Source
scopus
Published In
Methods (San Diego, Calif.)
Volume
64
Issue
2
Publish Date
2013
Start Page
129
End Page
136
DOI
10.1016/j.ymeth.2013.06.034

Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer.

Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial.Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS).With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit.The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.

Authors
Armstrong, AJ; Häggman, M; Stadler, WM; Gingrich, JR; Assikis, V; Polikoff, J; Damber, JE; Belkoff, L; Nordle, Ö; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Häggman, M, Stadler, WM, Gingrich, JR, Assikis, V, Polikoff, J, Damber, JE, Belkoff, L, Nordle, Ö, Forsberg, G, Carducci, MA, and Pili, R. "Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 19.24 (December 2013): 6891-6901.
PMID
24255071
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
19
Issue
24
Publish Date
2013
Start Page
6891
End Page
6901
DOI
10.1158/1078-0432.CCR-13-1581

Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial

Authors
Araujo, JC; Trudel, GC; Saad, F; Armstrong, AJ; Yu, EY; Bellmunt, J; Wilding, G; McCaffrey, J; Serrano, SV; Matveev, VB; Efstathiou, E; Oudard, S; Morris, MJ; Sizer, B; Goebell, PJ; Heidenreich, A; de Bono, JS; Begbie, S; Hong, JH; Richardet, E; Gallardo, E; Paliwal, P; Durham, S; Cheng, S; Logothetis, CJ
MLA Citation
Araujo, JC, Trudel, GC, Saad, F, Armstrong, AJ, Yu, EY, Bellmunt, J, Wilding, G, McCaffrey, J, Serrano, SV, Matveev, VB, Efstathiou, E, Oudard, S, Morris, MJ, Sizer, B, Goebell, PJ, Heidenreich, A, de Bono, JS, Begbie, S, Hong, JH, Richardet, E, Gallardo, E, Paliwal, P, Durham, S, Cheng, S, and Logothetis, CJ. "Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial." The Lancet Oncology 14.13 (December 2013): 1307-1316.
Source
crossref
Published In
The Lancet. Oncology
Volume
14
Issue
13
Publish Date
2013
Start Page
1307
End Page
1316
DOI
10.1016/S1470-2045(13)70479-0

Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells.

The relationship between the cells that initiate cancer and the cancer stem-like cells that propagate tumors has been poorly defined. In a human prostate tissue transformation model, basal cells expressing the oncogenes Myc and myristoylated AKT can initiate heterogeneous tumors. Tumors contain features of acinar-type adenocarcinoma with elevated eIF4E-driven protein translation and squamous cell carcinoma marked by activated beta-catenin. Lentiviral integration site analysis revealed that alternative histological phenotypes can be clonally derived from a common cell of origin. In advanced disease, adenocarcinoma can be propagated by self-renewing tumor cells with an androgen receptor-low immature luminal phenotype in the absence of basal-like cells. These data indicate that advanced prostate adenocarcinoma initiated in basal cells can be maintained by luminal-like tumor-propagating cells. Determining the cells that maintain human prostate adenocarcinoma and the signaling pathways characterizing these tumor-propagating cells is critical for developing effective therapeutic strategies against this population.

Authors
Stoyanova, T; Cooper, AR; Drake, JM; Liu, X; Armstrong, AJ; Pienta, KJ; Zhang, H; Kohn, DB; Huang, J; Witte, ON; Goldstein, AS
MLA Citation
Stoyanova, T, Cooper, AR, Drake, JM, Liu, X, Armstrong, AJ, Pienta, KJ, Zhang, H, Kohn, DB, Huang, J, Witte, ON, and Goldstein, AS. "Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells." Proceedings of the National Academy of Sciences of the United States of America 110.50 (December 2013): 20111-20116.
PMID
24282295
Source
epmc
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
110
Issue
50
Publish Date
2013
Start Page
20111
End Page
20116
DOI
10.1073/pnas.1320565110

Prostate cancer, version 1.2014.

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

Authors
Mohler, JL; Kantoff, PW; Armstrong, AJ; Bahnson, RR; Cohen, M; D'Amico, AV; Eastham, JA; Enke, CA; Farrington, TA; Higano, CS; Horwitz, EM; Kawachi, MH; Kuettel, M; Lee, RJ; Macvicar, GR; Malcolm, AW; Miller, D; Plimack, ER; Pow-Sang, JM; Richey, S; Roach, M; Rohren, E; Rosenfeld, S; Small, EJ; Srinivas, S; Stein, C; Strope, SA; Tward, J; Walsh, PC; Shead, DA; Ho, M; National comprehensive cancer network,
MLA Citation
Mohler, JL, Kantoff, PW, Armstrong, AJ, Bahnson, RR, Cohen, M, D'Amico, AV, Eastham, JA, Enke, CA, Farrington, TA, Higano, CS, Horwitz, EM, Kawachi, MH, Kuettel, M, Lee, RJ, Macvicar, GR, Malcolm, AW, Miller, D, Plimack, ER, Pow-Sang, JM, Richey, S, Roach, M, Rohren, E, Rosenfeld, S, Small, EJ, Srinivas, S, Stein, C, Strope, SA, Tward, J, Walsh, PC, Shead, DA, Ho, M, and National comprehensive cancer network, . "Prostate cancer, version 1.2014." Journal of the National Comprehensive Cancer Network : JNCCN 11.12 (December 2013): 1471-1479.
PMID
24335682
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
11
Issue
12
Publish Date
2013
Start Page
1471
End Page
1479
DOI
10.6004/jnccn.2013.0174

Development of a method to isolate circulating tumor cells using mesenchymal-based capture.

Epithelial tumor cells can become mesenchymal cells and vice versa via phenotypic transitions, a process known as epithelial plasticity. We postulate that during the process of metastasis, circulating tumor cells (CTCs) lose their epithelial phenotype and acquire a mesenchymal phenotype that may not be sufficiently captured by existing epithelial-based CTC technologies. We report here on the development of a novel CTC capture method, based on the biology of epithelial plasticity, which isolates cells based on OB-cadherin cell surface expression. Using this mesenchymal-based assay, OB-cadherin cellular events are detectable in men with metastatic prostate cancer and are less common in healthy volunteers. This method may complement existing epithelial-based methods and may be particularly useful in patients with bone metastases.

Authors
Bitting, RL; Boominathan, R; Rao, C; Kemeny, G; Foulk, B; Garcia-Blanco, MA; Connelly, M; Armstrong, AJ
MLA Citation
Bitting, RL, Boominathan, R, Rao, C, Kemeny, G, Foulk, B, Garcia-Blanco, MA, Connelly, M, and Armstrong, AJ. "Development of a method to isolate circulating tumor cells using mesenchymal-based capture." Methods (San Diego, Calif.) 64.2 (December 2013): 129-136.
PMID
23845299
Source
epmc
Published In
Methods (San Diego, Calif.)
Volume
64
Issue
2
Publish Date
2013
Start Page
129
End Page
136
DOI
10.1016/j.ymeth.2013.06.034

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.

BACKGROUND: Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown. METHODS: We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. RESULTS: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. CONCLUSION: Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, M; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, M, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Clin Genitourin Cancer 11.4 (December 2013): 397-406.
PMID
23830964
Source
pubmed
Published In
Clin Genitourin Cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
397
End Page
406
DOI
10.1016/j.clgc.2013.05.007

Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer.

Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer (PCa) cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating 'response' (that is, 10% decrease in peripheral blood mononuclear cell (PBMC) global 5-methyl cytosine (5(me)C) content) was observed in <3 patients in cohort 1. Cohorts 1 and 2 received disulfiram 250 mg and 500 mg daily, respectively. The primary end point was the proportion of subjects with a demethylation response. Secondary end points included the rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.Changes in global 5(me)C content were observed in two of nine patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only five subjects were on trial for 6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events (three per cohort). Three of the responders displayed pretreatment instability in their 5(me)C content.A minority of patients had transient global PBMC demethylation changes. Instability in 5(me)C may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.

Authors
Schweizer, MT; Lin, J; Blackford, A; Bardia, A; King, S; Armstrong, AJ; Rudek, MA; Yegnasubramanian, S; Carducci, MA
MLA Citation
Schweizer, MT, Lin, J, Blackford, A, Bardia, A, King, S, Armstrong, AJ, Rudek, MA, Yegnasubramanian, S, and Carducci, MA. "Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer." Prostate Cancer and Prostatic Diseases 16.4 (December 2013): 357-361.
PMID
23958896
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
357
End Page
361
DOI
10.1038/pcan.2013.28

Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial.

Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497.Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]).The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients.Bristol-Myers Squibb.

Authors
Araujo, JC; Trudel, GC; Saad, F; Armstrong, AJ; Yu, EY; Bellmunt, J; Wilding, G; McCaffrey, J; Serrano, SV; Matveev, VB; Efstathiou, E; Oudard, S; Morris, MJ; Sizer, B; Goebell, PJ; Heidenreich, A; de Bono, JS; Begbie, S; Hong, JH; Richardet, E; Gallardo, E; Paliwal, P; Durham, S; Cheng, S; Logothetis, CJ
MLA Citation
Araujo, JC, Trudel, GC, Saad, F, Armstrong, AJ, Yu, EY, Bellmunt, J, Wilding, G, McCaffrey, J, Serrano, SV, Matveev, VB, Efstathiou, E, Oudard, S, Morris, MJ, Sizer, B, Goebell, PJ, Heidenreich, A, de Bono, JS, Begbie, S, Hong, JH, Richardet, E, Gallardo, E, Paliwal, P, Durham, S, Cheng, S, and Logothetis, CJ. "Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial." The Lancet. Oncology 14.13 (December 2013): 1307-1316.
PMID
24211163
Source
epmc
Published In
The Lancet. Oncology
Volume
14
Issue
13
Publish Date
2013
Start Page
1307
End Page
1316
DOI
10.1016/s1470-2045(13)70479-0

Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: Implications for prior therapy in clinical trials

Objectives: Abiraterone acetate (AA) is a CYP17 inhibitor of androgen synthesis approved for use following docetaxel for metastatic castration-resistant prostate cancer (mCRPC); evaluation in the pre-docetaxel setting is ongoing. Given that the reported efficacy of AA is lower following docetaxel vs. pre-docetaxel, the potential exists for cross resistance given docetaxel's partly androgen receptor targeting activity. The efficacy of docetaxel following ketoconazole (KC), a weaker and nonspecific inhibitor of CYP17, may provide some insights into this potential interaction. We retrospectively evaluated the efficacy of every 3-week docetaxel with prednisone (DP) in mCRPC previously exposed to KC compared to KC-naive patients. Materials and methods: A randomized phase II trial of men with mCRPC treated with DP + AT-101 (bcl-2 inhibitor) vs. DP plus placebo was analyzed. Both arms were combined for analysis as no significant differences were seen. Overall survival (OS), progression-free survival (PFS), objective response (ORR), pain, and prostate-specific antigen (PSA) response rates were estimated with and without prior KC. Cox proportional hazards regression models were used to estimate the effect of covariates on OS. Results: Of 220 evaluable men, 40 (18.2%) received prior KC. The median OS with DP-based therapy of KC-naive patients (18.3 months, 95% CI: 15.0, 24.5) and post-KC patients (17.0 months, 95% CI: 9.9, 20.4) was not statistically different (P = 0.20). After controlling for prognostic classifications, analyses demonstrated consistent trends for worsening of OS after KC, with (hazard ratios (HRs) 1.33-1.46. Similar unfavorable trends were observed for ORR, PSA declines, and PFS. Conclusions: In this hypothesis-generating analysis, patients treated with docetaxel-based chemotherapy following prior KC had numerically and consistently worse outcomes than patients not exposed to prior KC. Although the estimated differences did not attain statistical significance, evaluation of outcomes with docetaxel in particular, and all classes of novel and emerging agents following AA, is of clinical importance, given its more potent androgen synthesis inhibition compared with KC. Drug development should take into account the potential impact of previous therapy. © 2013 Elsevier Inc.

Authors
Pond, GR; Armstrong, AJ; Galsky, MD; Wood, BA; Leopold, L; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Galsky, MD, Wood, BA, Leopold, L, and Sonpavde, G. "Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: Implications for prior therapy in clinical trials." Urologic Oncology: Seminars and Original Investigations 31.8 (November 1, 2013): 1457-1463.
Source
scopus
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
8
Publish Date
2013
Start Page
1457
End Page
1463
DOI
10.1016/j.urolonc.2012.02.008

Clinical phenotypes of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is defined as prostate cancer that no longer responds to androgen deprivation therapy. At the genome level, CRPC is a heterogeneous disease that is marked by a range of genetic and epigenetic lesions. These lesions differ from patient to patient, but have common pathway-based themes. Clinically, a range of phenotypic presentations or subtypes of CRPC are observed that mirror this underlying heterogeneity as the disease progresses; each phenotype carries a different prognosis and different implications for treatment. In this review, we discuss the clinical subtypes of CRPC based on histology; the presence of metastatic disease and pattern of spread; patient-reported symptoms; and levels of biomarkers, such as serum bone turn- over biomarkers, prostate-specific antigen, circulating tumor cell enumeration, and neuroendocrine biomarkers. We then address the potential relationship between these clinical phenotypes (with their underlying molecular subtypes) and therapeutic decision- making and prognosis, as well as ongoing research strategies.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Clinical phenotypes of castration-resistant prostate cancer." Clinical advances in hematology & oncology : H&O 11.11 (November 2013): 707-718. (Review)
PMID
24896544
Source
epmc
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
11
Issue
11
Publish Date
2013
Start Page
707
End Page
718

Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy.

Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy.Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC).The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively.A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.

Authors
Halabi, S; Lin, C-Y; Small, EJ; Armstrong, AJ; Kaplan, EB; Petrylak, D; Sternberg, CN; Shen, L; Oudard, S; de Bono, J; Sartor, O
MLA Citation
Halabi, S, Lin, C-Y, Small, EJ, Armstrong, AJ, Kaplan, EB, Petrylak, D, Sternberg, CN, Shen, L, Oudard, S, de Bono, J, and Sartor, O. "Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy." Journal of the National Cancer Institute 105.22 (November 2013): 1729-1737.
PMID
24136890
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
105
Issue
22
Publish Date
2013
Start Page
1729
End Page
1737
DOI
10.1093/jnci/djt280

Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy.

Prostate-specific antigen (PSA) kinetics, and more specifically a ≥ 30% decline in PSA within 3 months after initiation of first-line chemotherapy with docetaxel, are associated with improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). The objective of this analysis was to evaluate post-treatment PSA kinetics as surrogates for OS in patients receiving second-line chemotherapy.Data from a phase III trial of patients with mCRPC randomly assigned to cabazitaxel plus prednisone (C + P) or mitoxantrone plus prednisone were used. PSA decline (≥ 30% and ≥ 50%), velocity, and rise within the first 3 months of treatment were evaluated as surrogates for OS. The Prentice criteria, proportion of treatment explained (PTE), and meta-analytic approaches were used as measures of surrogacy.The observed hazard ratio (HR) for death for patients treated with C + P was 0.66 (95% CI, 0.55 to 0.79; P < .001). Furthermore, a ≥ 30% decline in PSA was a statistically significant predictor of OS (HR for death, 0.52; 95% CI, 0.43 to 0.64; P < .001). Adjusting for treatment effect, the HR for a ≥ 30% PSA decline was 0.50 (95% CI, 0.40 to 0.62; P < .001), but treatment remained statistically significant, thus failing the third Prentice criterion. The PTE for a ≥ 30% decline in PSA was 0.34 (95% CI, 0.11 to 0.56), indicating a lack of surrogacy for OS. The values of R(2) were < 1, suggesting that PSA decline was not surrogate for OS.Surrogacy for any PSA-based end point could not be demonstrated in this analysis. Thus, the benefits of cabazitaxel in mediating a survival benefit are not fully captured by early PSA changes.

Authors
Halabi, S; Armstrong, AJ; Sartor, O; de Bono, J; Kaplan, E; Lin, C-Y; Solomon, NC; Small, EJ
MLA Citation
Halabi, S, Armstrong, AJ, Sartor, O, de Bono, J, Kaplan, E, Lin, C-Y, Solomon, NC, and Small, EJ. "Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 31.31 (November 2013): 3944-3950.
PMID
24101043
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
31
Publish Date
2013
Start Page
3944
End Page
3950
DOI
10.1200/JCO.2013.50.3201

Rationing in urologic oncology: lessons from sipuleucel-T for advanced prostate cancer.

OBJECTIVES: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. MATERIALS AND METHODS: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. RESULTS AND CONCLUSIONS: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general.

Authors
Peppercorn, J; Armstrong, A; Zaas, DW; George, D
MLA Citation
Peppercorn, J, Armstrong, A, Zaas, DW, and George, D. "Rationing in urologic oncology: lessons from sipuleucel-T for advanced prostate cancer." Urol Oncol 31.7 (October 2013): 1079-1084.
PMID
22305627
Source
pubmed
Published In
Urol Oncol
Volume
31
Issue
7
Publish Date
2013
Start Page
1079
End Page
1084
DOI
10.1016/j.urolonc.2011.12.022

Highlights in advanced prostate cancer from the 2013 American Urological Association Annual Meeting and the 2013 American Society of Clinical Oncology Annual Meeting: commentary.

Authors
George, DJ; Armstrong, AJ; Harrison, MR
MLA Citation
George, DJ, Armstrong, AJ, and Harrison, MR. "Highlights in advanced prostate cancer from the 2013 American Urological Association Annual Meeting and the 2013 American Society of Clinical Oncology Annual Meeting: commentary." Clin Adv Hematol Oncol 11 Suppl 14.9 (September 2013): 16-22.
PMID
25856023
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
11 Suppl 14
Issue
9
Publish Date
2013
Start Page
16
End Page
22

Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide.

Abiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance occurs is unknown.Multicentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response.Thirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56-84 years); 70% had ECOG performance status of 0-1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6-95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1-52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks [95% confidence interval (CI) 10.7-20.2]. Median overall survival was 50.1 weeks (95% CI 28.3-72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide.In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone.

Authors
Noonan, KL; North, S; Bitting, RL; Armstrong, AJ; Ellard, SL; Chi, KN
MLA Citation
Noonan, KL, North, S, Bitting, RL, Armstrong, AJ, Ellard, SL, and Chi, KN. "Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide." Annals of Oncology : Official Journal of the European Society for Medical Oncology 24.7 (July 2013): 1802-1807.
PMID
23585511
Source
epmc
Published In
Annals of Oncology
Volume
24
Issue
7
Publish Date
2013
Start Page
1802
End Page
1807
DOI
10.1093/annonc/mdt138

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer.

Authors
Bitting, RL; Armstrong, AJ
MLA Citation
Bitting, RL, and Armstrong, AJ. "Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer." Endocrine Related Cancer 20.3 (June 2013): R83-R99. (Review)
PMID
23456430
Source
epmc
Published In
Endocrine Related Cancer
Volume
20
Issue
3
Publish Date
2013
Start Page
R83
End Page
R99
DOI
10.1530/erc-12-0394

Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC).

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Ko, JH; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Ko, JH, and Armstrong, AJ. "Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma

Authors
Armstrong, AJ; Halabi, S; Eisen, T; Stadler, WM; Jones, RR; Vaishampayan, UN; Garcia, JA; Hawkins, RE; Kollmannsberger, CK; Lusk, C; Broderick, S; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Eisen, T, Stadler, WM, Jones, RR, Vaishampayan, UN, Garcia, JA, Hawkins, RE, Kollmannsberger, CK, Lusk, C, Broderick, S, and George, DJ. "ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy

Authors
Halabi, S; Lin, C-Y; Small, EJ; Armstrong, AJ; Kaplan, EB; Petrylak, DP; Sternberg, CN; Shen, L; Oudard, S; De Bono, JS; Sartor, AO
MLA Citation
Halabi, S, Lin, C-Y, Small, EJ, Armstrong, AJ, Kaplan, EB, Petrylak, DP, Sternberg, CN, Shen, L, Oudard, S, De Bono, JS, and Sartor, AO. "A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Association of bone scan index (BSI) with prognostic biomarkers and survival in men with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective randomized controlled trial of tasquinimod

Authors
Armstrong, AJ; Kaboteh, R; Carducci, MA; Damber, J-E; Stadler, WM; Mats, H; Edenbrandt, L; Forsberg, G; Nordle, O; Pili, R; Morris, MJ
MLA Citation
Armstrong, AJ, Kaboteh, R, Carducci, MA, Damber, J-E, Stadler, WM, Mats, H, Edenbrandt, L, Forsberg, G, Nordle, O, Pili, R, and Morris, MJ. "Association of bone scan index (BSI) with prognostic biomarkers and survival in men with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective randomized controlled trial of tasquinimod." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Impact of prior docetaxel (D) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).

Authors
Higano, CS; Armstrong, AJ; Cooperberg, MR; Kantoff, PW; Bailen, J; Concepcion, RS; Kassabian, V; Dakhil, SR; Finkelstein, SE; Vacirca, JL; Rifkin, RM; Sandler, A; McCoy, C; Whitmore, JB; Tyler, C; Sartor, AO
MLA Citation
Higano, CS, Armstrong, AJ, Cooperberg, MR, Kantoff, PW, Bailen, J, Concepcion, RS, Kassabian, V, Dakhil, SR, Finkelstein, SE, Vacirca, JL, Rifkin, RM, Sandler, A, McCoy, C, Whitmore, JB, Tyler, C, and Sartor, AO. "Impact of prior docetaxel (D) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Reply to M A Khattak et al.

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Reply to M A Khattak et al." J Clin Oncol 31.7 (March 1, 2013): 972-973. (Letter)
PMID
23565533
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
31
Issue
7
Publish Date
2013
Start Page
972
End Page
973
DOI
10.1200/JCO.2012.47.7224

Prognostic and Predictive Markers in Metastatic Renal Cell Carcinoma Reply

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Prognostic and Predictive Markers in Metastatic Renal Cell Carcinoma Reply." JOURNAL OF CLINICAL ONCOLOGY 31.7 (March 1, 2013): 972-973.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
7
Publish Date
2013
Start Page
972
End Page
973
DOI
10.1200/JCO.2012.47.7224

Novel therapies for the treatment of advanced prostate cancer.

In recent years, great success has been achieved on many fronts in the treatment of men with metastatic castration-resistant prostate cancer (CRPC), including novel chemotherapeutics, immunotherapies, bone microenvironment-targeted agents, and hormonal therapies. Numerous agents are currently in early-phase clinical trial development for the treatment of advanced prostate cancer. These novel therapies target several areas of prostate tumor biology, including the upregulation of androgen signaling and biosynthesis, critical oncogenic intracellular pathways, epigenetic alterations, and cancer immunology. Importantly, the characterization of the prostate cancer genome offers the potential to exploit conserved genetic alterations, which may increase the efficacy of these targeted therapies. Predictive and prognostic biomarkers are urgently needed to maximize therapeutic efficacy and safety of these promising new treatments options in prostate cancer.

Authors
Clarke, JM; Armstrong, AJ
MLA Citation
Clarke, JM, and Armstrong, AJ. "Novel therapies for the treatment of advanced prostate cancer." Curr Treat Options Oncol 14.1 (March 2013): 109-126. (Review)
PMID
23322116
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
14
Issue
1
Publish Date
2013
Start Page
109
End Page
126
DOI
10.1007/s11864-012-0222-4

Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors.

PURPOSE: The activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population. METHODS: We conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed. RESULTS: Twenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%). CONCLUSIONS: Single-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted.

Authors
Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ; Armstrong, AJ
MLA Citation
Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, George, DJ, and Armstrong, AJ. "Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors." Clinical Genitourinary Cancer 11.1 (March 2013): 45-50.
PMID
23041453
Source
epmc
Published In
Clinical Genitourinary Cancer
Volume
11
Issue
1
Publish Date
2013
Start Page
45
End Page
50
DOI
10.1016/j.clgc.2012.06.001

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, MT; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, MT, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." February 20, 2013.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6_suppl
Publish Date
2013
Start Page
105
End Page
105
DOI
10.1200/jco.2013.31.6_suppl.105

A model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (CRPC) for whom first-line chemotherapy failed

Authors
Halabi, S; Lin, C-Y; Small, EJ; Armstrong, AJ; Kaplan, EB; Petrylak, DP; Sternberg, CN; Shen, L; Oudard, S; De Bono, JS; Sartor, AO
MLA Citation
Halabi, S, Lin, C-Y, Small, EJ, Armstrong, AJ, Kaplan, EB, Petrylak, DP, Sternberg, CN, Shen, L, Oudard, S, De Bono, JS, and Sartor, AO. "A model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (CRPC) for whom first-line chemotherapy failed." February 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6
Publish Date
2013
DOI
10.1200/jco.2013.31.6_suppl.24

A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa)

Authors
Schweizer, MT; Bardia, A; Blackford, AL; Lin, J; Armstrong, AJ; King, S; Rudek, MA; Yegnasubramanian, ST; Carducci, MA
MLA Citation
Schweizer, MT, Bardia, A, Blackford, AL, Lin, J, Armstrong, AJ, King, S, Rudek, MA, Yegnasubramanian, ST, and Carducci, MA. "A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa)." February 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6
Publish Date
2013
DOI
10.1200/jco.2013.31.6_suppl.219

Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor

Authors
Scher, HI; Fizazi, K; Saad, F; Chi, KN; Taplin, M-E; Sternberg, CN; Armstrong, AJ; Hirmand, M; Forer, D; De Bono, JS
MLA Citation
Scher, HI, Fizazi, K, Saad, F, Chi, KN, Taplin, M-E, Sternberg, CN, Armstrong, AJ, Hirmand, M, Forer, D, and De Bono, JS. "Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor." February 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6
Publish Date
2013
DOI
10.1200/jco.2013.31.6_suppl.6

Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes.Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study.On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively.In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself.NCT00974311. [Table: see text].

Authors
Fizazi, K; Saad, F; Chi, KN; Taplin, ME; Sternberg, CN; Armstrong, AJ; Hirmand, M; Forer, D; De Bono, JS
MLA Citation
Fizazi, K, Saad, F, Chi, KN, Taplin, ME, Sternberg, CN, Armstrong, AJ, Hirmand, M, Forer, D, and De Bono, JS. "Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.6_suppl (February 2013): 6-.
PMID
28137161
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6_suppl
Publish Date
2013
Start Page
6

A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines.To determine if D leads to demethylation changes [i.e. decreased global 5(me)C DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating "response" (i.e. >10% decrease in global 5(me)C content) in <3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed >50% rise over baseline and >2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability.Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had >10% decrease in global 5(me)C content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms.A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population.NCT01118741.

Authors
Bardia, A; Blackford, AL; Lin, J; Armstrong, AJ; King, S; Rudek, MA; Yegnasubramanian, ST; Carducci, MA
MLA Citation
Bardia, A, Blackford, AL, Lin, J, Armstrong, AJ, King, S, Rudek, MA, Yegnasubramanian, ST, and Carducci, MA. "A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.6_suppl (February 2013): 219-.
PMID
28137035
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6_suppl
Publish Date
2013
Start Page
219

A model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (CRPC) for whom first-line chemotherapy failed.

24 Background: Several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC. The primary objective was to develop and validate a prognostic model that can be used to predict OS in men who have failed first-line chemotherapy.Data was used from a phase III trial of 755 mCRPC men who had developed progressive disease following first-line chemotherapy and were randomized to cabazitaxel plus prednisone or mitoxantrone plus prednisone (TROPIC trial). The data was randomly split into training (n=507) and testing (n=248) sets. A separate data, consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone, was used as the validation set (SPARC trial). Penalized regression method was used to identify important prognostic factors. Adaptive Lasso selected nine variables of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.29) and high (>= -1.29) risk groups in the testing datasets. The model was assessed for its predictive accuracy using time dependent area under the curve (AUC) on the testing sets (TROPIC and SPARC trials).The final selected model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. In the TROPIC testing set, the median OS in high and low risk groups were 11 and 17 months, respectively, with a hazard ratio (HR)=2.47 (p-value<0.0001). Using the SPARC set, the median OS were 11 and 20 months in the high and low risk groups, respectively, with a HR=1.94 (p<0.0001). The time dependent AUC were 0.73 and 0.70 on the testing sets.A prognostic model of OS in the post-docetaxel mCRPC setting was developed and validated and risk groups were identified. This model can be used to select patients based on their prognosis to participate in clinical trials. Prospective validation is needed.

Authors
Lin, CY; Small, EJ; Armstrong, AJ; Kaplan, EB; Petrylak, DP; Sternberg, CN; Shen, L; Oudard, S; De Bono, JS; Sartor, AO
MLA Citation
Lin, CY, Small, EJ, Armstrong, AJ, Kaplan, EB, Petrylak, DP, Sternberg, CN, Shen, L, Oudard, S, De Bono, JS, and Sartor, AO. "A model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (CRPC) for whom first-line chemotherapy failed." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.6_suppl (February 2013): 24-.
PMID
28136957
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6_suppl
Publish Date
2013
Start Page
24

Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial.

LBA8 Background: SRC kinases may contribute to androgen independence of mCRPC.Dasatinib (DAS) inhibits tyrosine kinases including SRC kinases with preclinical evidence for antimetastatic activity, inhibition of osteoclast function in tumor microenvironment, and synergistic activity with docetaxel (D). In phase I/II trials of mCRPC patients (pts), DAS in combination with D had an acceptable safety profile with objective response rates (ORR) improved over historical data and decreased levels of bone turnover markers.READY was a multinational, randomized, double-blinded, placebo-controlled, phase III study. Pts with mCRPC (n = 1,522) were randomized (1:1) to receive either D 75 mg/m(2)q3wk + prednisone with double-blinded DAS 100 mg qd (DAS/D, n = 762) or placebo (PBO/D, n = 760). Primary endpoint was overall survival (OS). Secondary endpoints were ORR, time to first skeletal-related event (TFSRE), time to prostate-specific antigen progression (TPSAP), urinary N-telopeptide (uNTX) reduction, pain reduction, progression-free survival (PFS), and safety.No OS difference between DAS/D and PBO/D (median, 21.5 vs. 21.2 mos; hazard ratio [HR], 0.99; log-rank P = 0.90) was observed. Results of secondary endpoints for DAS/D vs. PBO/D were: ORR (30.5 vs. 31.9%); TFSRE (median, not reached vs. 31.1 mos; HR, 0.81 [95% CI, 0.64-1.02]); uNTX reduction (66.0 vs. 60.6%); PFS (median, 11.8 vs. 11.1 mos; HR, 0.92); TPSAP (median, 8.0 vs. 7.6 mos; HR, 0.91), and pain reduction (66.6 vs. 71.5%). Twenty-three percent of DAS/D and 14% of PBO/D pts received therapy for <3 mos. Most common AEs in DAS/D arm included diarrhea, fatigue, alopecia, and nausea. Grade 3-4 AEs of interest for DAS/D vs. PBO/D included anemia (8.0 vs.5.9%), neutropenia (6.2 vs. 5.5%), hypocalcemia (3.5 vs.3.1%), GI bleeding (2.6 vs.1.3%), and pleural effusion (1.3 vs. 0.4%).The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS. There was a modest reduction in the risk of TFSRE with DAS/D vs. PBO/D. With a median follow-up of 19 mos of 761 DAS/D-treated pts, no unexpected toxicities for DAS were observed.NCT00744497.

Authors
Trudel, GC; Saad, F; Armstrong, AJ; Yu, EY; Bellmunt, J; Wilding, G; McCaffrey, J; Serrano, SV; Matveev, V; Efstathiou, E; Oudard, S; Morris, MJ; Sizer, B; Goebell, PJ; De Bono, JS; Paliwal, P; Durham, S; Cheng, S; Logothetis, C
MLA Citation
Trudel, GC, Saad, F, Armstrong, AJ, Yu, EY, Bellmunt, J, Wilding, G, McCaffrey, J, Serrano, SV, Matveev, V, Efstathiou, E, Oudard, S, Morris, MJ, Sizer, B, Goebell, PJ, De Bono, JS, Paliwal, P, Durham, S, Cheng, S, and Logothetis, C. "Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.6_suppl (February 2013): LBA8-.
PMID
28136933
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
6_suppl
Publish Date
2013
Start Page
LBA8

Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease.

Radium-223 chloride ((223)Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), (223)Ra delivers a high quantity of energy per track length with short tissue penetration.This review describes the mechanism, radiobiology, and preclinical development of (223)Ra and discusses the clinical data currently available regarding its safety and efficacy profile.Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database.Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, (223)Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, (223)Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents.

Authors
Harrison, MR; Wong, TZ; Armstrong, AJ; George, DJ
MLA Citation
Harrison, MR, Wong, TZ, Armstrong, AJ, and George, DJ. "Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease." Cancer Management and Research 5 (January 8, 2013): 1-14.
PMID
23326203
Source
epmc
Published In
Cancer Management and Research
Volume
5
Publish Date
2013
Start Page
1
End Page
14
DOI
10.2147/CMAR.S25537

A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer.

Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer.In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes.Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days.Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents.

Authors
Whang, YE; Armstrong, AJ; Rathmell, WK; Godley, PA; Kim, WY; Pruthi, RS; Wallen, EM; Crane, JM; Moore, DT; Grigson, G; Morris, K; Watkins, CP; George, DJ
MLA Citation
Whang, YE, Armstrong, AJ, Rathmell, WK, Godley, PA, Kim, WY, Pruthi, RS, Wallen, EM, Crane, JM, Moore, DT, Grigson, G, Morris, K, Watkins, CP, and George, DJ. "A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer." Urologic Oncology 31.1 (January 2013): 82-86.
PMID
21396844
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
1
Publish Date
2013
Start Page
82
End Page
86
DOI
10.1016/j.urolonc.2010.09.018

Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer.

With the surge in therapeutic options for men with castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making, highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Predictive biomarkers are factors related to the disease or the host that are associated with improvements in outcomes, such as survival, due to specific therapies. Such biomarkers have become of paramount importance in oncology to maximize the benefits of novel systemic agents while minimizing harm to individual patients and the costs to society. Given the number of newly approved and expensive systemic therapies, including novel hormonal therapies, chemotherapies, immunotherapies, and bone microenvironment-targeting therapies, predictive biomarkers are needed to give physicians a more rational sense of matching the right patient to the right therapy sequence at a given time. There are currently no validated predictive biomarkers in CRPC. We discuss potential predictive biomarkers in men with CRPC and how these may be developed in the context of therapeutic clinical trials.

Authors
Bitting, RL; Armstrong, AJ
MLA Citation
Bitting, RL, and Armstrong, AJ. "Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer." Cancer Journal (Sudbury, Mass.) 19.1 (January 2013): 25-33. (Review)
PMID
23337754
Source
epmc
Published In
Cancer Journal (Sudbury, Mass.)
Volume
19
Issue
1
Publish Date
2013
Start Page
25
End Page
33
DOI
10.1097/ppo.0b013e31827e0b9c

New and emerging therapies for bone metastases in genitourinary cancers

Context: Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality. Objective: The objective of this review is to discuss the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies. Evidence acquisition: We reviewed the relevant medical literature, with a particular emphasis on prospective randomized controlled trials. Much of the relevant clinical trial data focus on prostate cancer (PCa). We provide a nonsystematic review and our perspective on the available data. Evidence synthesis: Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for skeletal metastases often features a combination of disease-specific therapy and bone-targeted therapy. Some agents, such as the radiopharmaceutical radium-223, blur the line between those categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases. Zoledronic acid, a bisphosphonate, is approved for the prevention of skeletal events caused by solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that inactivates receptor activator of nuclear factor-κB ligand and is approved for the same indication. Beta-emitting radiopharmaceuticals can be effective for the palliation of pain caused by bone metastases, but their use is often limited by marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in select men with castration-resistant PCa metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET). Conclusions: Bone metastases cause considerable morbidity and mortality among patients with genitourinary malignancies. Optimal management requires consideration of bone-targeted therapy as well as disease-specific therapy. Further research is needed to optimize the use of existing agents and to define the therapeutic potential of novel targets. © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Authors
Saylor, PJ; Armstrong, AJ; Fizazi, K; Freedland, S; Saad, F; Smith, MR; Tombal, B; Pienta, K
MLA Citation
Saylor, PJ, Armstrong, AJ, Fizazi, K, Freedland, S, Saad, F, Smith, MR, Tombal, B, and Pienta, K. "New and emerging therapies for bone metastases in genitourinary cancers." European Urology 63.2 (2013): 309-320.
Source
scival
Published In
European Urology
Volume
63
Issue
2
Publish Date
2013
Start Page
309
End Page
320
DOI
10.1016/j.eururo.2012.10.007

A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer

Objectives: Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer. Methods: In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes. Results: Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days. Conclusions: Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents. © 2013 Elsevier Inc.

Authors
Whang, YE; Armstrong, AJ; Rathmell, WK; Godley, PA; Kim, WY; Pruthi, RS; Wallen, EM; Crane, JM; Moore, DT; Grigson, G; Morris, K; Watkins, CP; George, DJ
MLA Citation
Whang, YE, Armstrong, AJ, Rathmell, WK, Godley, PA, Kim, WY, Pruthi, RS, Wallen, EM, Crane, JM, Moore, DT, Grigson, G, Morris, K, Watkins, CP, and George, DJ. "A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer." Urologic Oncology: Seminars and Original Investigations 31.1 (2013): 82-86.
Source
scival
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
1
Publish Date
2013
Start Page
82
End Page
86
DOI
10.1016/j.urolonc.2010.09.018

Rationing in urologic oncology: Lessons from sipuleucel-T for advanced prostate cancer

Objectives: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. Materials and methods: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. Results and conclusions: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general. © 2013 Elsevier Inc.

Authors
Peppercorn, J; Armstrong, A; Zaas, DW; George, D
MLA Citation
Peppercorn, J, Armstrong, A, Zaas, DW, and George, D. "Rationing in urologic oncology: Lessons from sipuleucel-T for advanced prostate cancer." Urologic Oncology: Seminars and Original Investigations 31.7 (2013): 1079-1084.
Source
scival
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
7
Publish Date
2013
Start Page
1079
End Page
1084
DOI
10.1016/j.urolonc.2011.12.022

Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel-based chemotherapy.

UNLABELLED: What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted. OBJECTIVE: • Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. PATIENTS AND METHODS: • A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. RESULTS: • C-reactive protein was independently prognostic for OS and PFS (P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. CONCLUSIONS: • Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted.

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Leopold, L; Galsky, MD; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Leopold, L, Galsky, MD, and Sonpavde, G. "Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel-based chemotherapy." BJU Int 110.11 Pt B (December 2012): E461-E468.
PMID
22520631
Source
pubmed
Published In
Bju Int
Volume
110
Issue
11 Pt B
Publish Date
2012
Start Page
E461
End Page
E468
DOI
10.1111/j.1464-410X.2012.11148.x

ASSOCIATION OF BASELINE CORTICOSTEROID WITH OUTCOMES IN A MULTIVARIATE ANALYSIS OF THE PHASE 3 AFFIRM STUDY OF ENZALUTAMIDE (ENZA), AN ANDROGEN RECEPTOR SIGNALING INHIBITOR (ARSI)

Authors
Scher, HI; Fizazi, K; Saad, F; Chi, K; Taplin, M; Sternberg, CN; Armstrong, AJ; Hirmand, M; Selby, B; de Bono, JS
MLA Citation
Scher, HI, Fizazi, K, Saad, F, Chi, K, Taplin, M, Sternberg, CN, Armstrong, AJ, Hirmand, M, Selby, B, and de Bono, JS. "ASSOCIATION OF BASELINE CORTICOSTEROID WITH OUTCOMES IN A MULTIVARIATE ANALYSIS OF THE PHASE 3 AFFIRM STUDY OF ENZALUTAMIDE (ENZA), AN ANDROGEN RECEPTOR SIGNALING INHIBITOR (ARSI)." September 2012.
Source
wos-lite
Published In
Annals of Oncology
Volume
23
Publish Date
2012
Start Page
297
End Page
297

Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy.

OBJECTIVES: The association of a change in serum alkaline phosphatase (ALP) with overall survival OS in men with metastatic castration-resistant prostate cancer (CRPC) receiving chemotherapy is unknown. We evaluated the association of changes in ALP within 90 days with OS in men with CRPC and bone metastases treated with docetaxel or mitoxantrone in the TAX327 trial. MATERIALS AND METHODS: Eligible patients included those with bony metastatic disease, baseline ALP ≥ 120 u/L (upper limit of normal) and ≥2 post-therapy measurements of ALP available. Survival was estimated using the Kaplan-Meier method and prognostic potential of change in ALP was evaluated using Cox proportional hazards regression. Surrogacy was calculated by the Likelihood Reduction Factor. RESULTS: 601 patients met the eligibility criteria. By day 90, 159 patients had ALP normalization (<120 u/L) and 442 patients did not normalize. Normalization of ALP remained prognostic for OS after adjusting for PSA decline ≥ 30% by day 90 (HR 0.79, 95% CI = 0.65-0.97, P = 0.022). Increase in ALP remained prognostic for OS when adjusting for PSA increase ≥ 50% by day 90 (HR 1.69, 95% CI = 1.33-2.14, P < 0.001). ALP changes did not meet criteria for surrogacy for OS. CONCLUSIONS: For men with CRPC, bone metastasis and high baseline ALP receiving docetaxel or mitoxantrone chemotherapy, normalization of ALP by day 90 was predictive of better survival independent of ≥30% PSA declines. An increase in ALP by day 90 was also predictive of poor survival independent of ≥50% PSA increase. Given the ready availability of ALP, the validation of our data is warranted.

Authors
Sonpavde, G; Pond, GR; Berry, WR; de Wit, R; Armstrong, AJ; Eisenberger, MA; Tannock, IF
MLA Citation
Sonpavde, G, Pond, GR, Berry, WR, de Wit, R, Armstrong, AJ, Eisenberger, MA, and Tannock, IF. "Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy." Urologic Oncology 30.5 (September 2012): 607-613.
PMID
20888271
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
30
Issue
5
Publish Date
2012
Start Page
607
End Page
613
DOI
10.1016/j.urolonc.2010.07.002

Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin.

PURPOSE: Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. PATIENTS AND METHODS: We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). RESULTS: Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). CONCLUSION: Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 30.27 (September 2012): 3402-3407.
PMID
22891270
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
27
Publish Date
2012
Start Page
3402
End Page
3407
DOI
10.1200/jco.2011.40.9631

Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

Authors
Mohler, JL; Armstrong, AJ; Bahnson, RR; Boston, B; Busby, JE; D'Amico, AV; Eastham, JA; Enke, CA; Farrington, T; Higano, CS; Horwitz, EM; Kantoff, PW; Kawachi, MH; Kuettel, M; Lee, RJ; MacVicar, GR; Malcolm, AW; Miller, D; Plimack, ER; Pow-Sang, JM; Roach, M; Rohren, E; Rosenfeld, S; Srinivas, S; Strope, SA; Tward, J; Twardowski, P; Walsh, PC; Ho, M; Shead, DA
MLA Citation
Mohler, JL, Armstrong, AJ, Bahnson, RR, Boston, B, Busby, JE, D'Amico, AV, Eastham, JA, Enke, CA, Farrington, T, Higano, CS, Horwitz, EM, Kantoff, PW, Kawachi, MH, Kuettel, M, Lee, RJ, MacVicar, GR, Malcolm, AW, Miller, D, Plimack, ER, Pow-Sang, JM, Roach, M, Rohren, E, Rosenfeld, S, Srinivas, S, Strope, SA, Tward, J, Twardowski, P, Walsh, PC, Ho, M, and Shead, DA. "Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines." Journal of the National Comprehensive Cancer Network : Jnccn 10.9 (September 2012): 1081-1087.
PMID
22956807
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
10
Issue
9
Publish Date
2012
Start Page
1081
End Page
1087
DOI
10.6004/jnccn.2012.0114

Increased survival with enzalutamide in prostate cancer after chemotherapy.

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).

Authors
Scher, HI; Fizazi, K; Saad, F; Taplin, M-E; Sternberg, CN; Miller, K; de Wit, R; Mulders, P; Chi, KN; Shore, ND; Armstrong, AJ; Flaig, TW; Fléchon, A; Mainwaring, P; Fleming, M; Hainsworth, JD; Hirmand, M; Selby, B; Seely, L; de Bono, JS; AFFIRM Investigators,
MLA Citation
Scher, HI, Fizazi, K, Saad, F, Taplin, M-E, Sternberg, CN, Miller, K, de Wit, R, Mulders, P, Chi, KN, Shore, ND, Armstrong, AJ, Flaig, TW, Fléchon, A, Mainwaring, P, Fleming, M, Hainsworth, JD, Hirmand, M, Selby, B, Seely, L, de Bono, JS, and AFFIRM Investigators, . "Increased survival with enzalutamide in prostate cancer after chemotherapy." The New England Journal of Medicine 367.13 (September 2012): 1187-1197.
PMID
22894553
Source
epmc
Published In
The New England Journal of Medicine
Volume
367
Issue
13
Publish Date
2012
Start Page
1187
End Page
1197
DOI
10.1056/nejmoa1207506

OPENACT: PHASE 2, OPEN-LABEL STUDY OF SIPULEUCEL-T IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER (MCRPC)

Authors
Corman, J; Dawson, N; Hall, S; Nabhan, C; Ferrari, A; Armstrong, AJ; Murdock, MI; Stewart, F; Sheikh, N; Petrylak, DP
MLA Citation
Corman, J, Dawson, N, Hall, S, Nabhan, C, Ferrari, A, Armstrong, AJ, Murdock, MI, Stewart, F, Sheikh, N, and Petrylak, DP. "OPENACT: PHASE 2, OPEN-LABEL STUDY OF SIPULEUCEL-T IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER (MCRPC)." September 2012.
Source
wos-lite
Published In
Annals of Oncology
Volume
23
Publish Date
2012
Start Page
311
End Page
311

ASSOCIATION OF PROGRESSION BY PROSTATE CANCER WORKING GROUP (PCWG)-2 CRITERIA AND SURVIVAL IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER

Authors
Sonpavde, G; Pond, GR; Armstrong, AJ; Galsky, MD; Wood, BA; Wang, S; Paolini, J; Lechuga, M; Smith, MR; Michaelson, MD
MLA Citation
Sonpavde, G, Pond, GR, Armstrong, AJ, Galsky, MD, Wood, BA, Wang, S, Paolini, J, Lechuga, M, Smith, MR, and Michaelson, MD. "ASSOCIATION OF PROGRESSION BY PROSTATE CANCER WORKING GROUP (PCWG)-2 CRITERIA AND SURVIVAL IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER." September 2012.
Source
wos-lite
Published In
Annals of Oncology
Volume
23
Publish Date
2012
Start Page
297
End Page
298

Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor

Authors
De Bono, JS; Fizazi, K; Saad, F; Taplin, M-E; Sternberg, CN; Miller, K; Mulders, P; Chi, KN; Armstrong, AJ; Hirmand, M; Selby, B; Scher, HI; Investigators, AFFIRM
MLA Citation
De Bono, JS, Fizazi, K, Saad, F, Taplin, M-E, Sternberg, CN, Miller, K, Mulders, P, Chi, KN, Armstrong, AJ, Hirmand, M, Selby, B, Scher, HI, and Investigators, AFFIRM. "Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Prostate-specific antigen decline (PSA) as a surrogate for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy

Authors
Halabi, S; Armstrong, AJ; Sartor, AO; De Bono, JS; Kaplan, EB; Small, EJ
MLA Citation
Halabi, S, Armstrong, AJ, Sartor, AO, De Bono, JS, Kaplan, EB, and Small, EJ. "Prostate-specific antigen decline (PSA) as a surrogate for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Isolation of circulating tumor cells using a novel EMT-based capture method.

Authors
Bitting, RL; Boominathan, R; Rao, C; Embree, E; George, DJ; Connelly, MC; Kemeny, G; Garcia-Blanco, M; Armstrong, AJ
MLA Citation
Bitting, RL, Boominathan, R, Rao, C, Embree, E, George, DJ, Connelly, MC, Kemeny, G, Garcia-Blanco, M, and Armstrong, AJ. "Isolation of circulating tumor cells using a novel EMT-based capture method." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial

Authors
Armstrong, AJ; Haggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Polikoff, J; Denmeade, SR; George, DJ; Andreou, C; Clark, WR; Sieber, P; Agajanian, R; Belkoff, L; Damber, J-E; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Haggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Polikoff, J, Denmeade, SR, George, DJ, Andreou, C, Clark, WR, Sieber, P, Agajanian, R, Belkoff, L, Damber, J-E, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial." 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO). June 1, 2012 - June 6, 2012. Chicago, IL.: AMER SOC CLINICAL ONCOLOGY, May 20, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

The STAMPEDE trial and celecoxib: how to adapt?

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "The STAMPEDE trial and celecoxib: how to adapt?." Lancet Oncol 13.5 (May 2012): 443-445.
PMID
22452892
Source
pubmed
Published In
The Lancet Oncology
Volume
13
Issue
5
Publish Date
2012
Start Page
443
End Page
445
DOI
10.1016/S1470-2045(12)70111-0

Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer.

CONTEXT: We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes. OBJECTIVE: In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy). EVIDENCE ACQUISITION: PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion. EVIDENCE SYNTHESIS: We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions. CONCLUSIONS: A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit.

Authors
Armstrong, AJ; Eisenberger, MA; Halabi, S; Oudard, S; Nanus, DM; Petrylak, DP; Sartor, AO; Scher, HI
MLA Citation
Armstrong, AJ, Eisenberger, MA, Halabi, S, Oudard, S, Nanus, DM, Petrylak, DP, Sartor, AO, and Scher, HI. "Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer." Eur Urol 61.3 (March 2012): 549-559. (Review)
PMID
22099611
Source
pubmed
Published In
Eur Urol
Volume
61
Issue
3
Publish Date
2012
Start Page
549
End Page
559
DOI
10.1016/j.eururo.2011.11.009

Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C-terminal autoinhibitory region.

Pannexin 1 (PANX1) channels mediate release of ATP, a "find-me" signal that recruits macrophages to apoptotic cells; PANX1 activation during apoptosis requires caspase-mediated cleavage of PANX1 at its C terminus, but how the C terminus inhibits basal channel activity is not understood. Here, we provide evidence suggesting that the C terminus interacts with the human PANX1 (hPANX1) pore and that cleavage-mediated channel activation requires disruption of this inhibitory interaction. Basally silent hPANX1 channels localized on the cell membrane could be activated directly by protease-mediated C-terminal cleavage, without additional apoptotic effectors. By serial deletion, we identified a C-terminal region just distal to the caspase cleavage site that is required for inhibition of hPANX1; point mutations within this small region resulted in partial activation of full-length hPANX1. Consistent with the C-terminal tail functioning as a pore blocker, we found that truncated and constitutively active hPANX1 channels could be inhibited, in trans, by the isolated hPANX1 C terminus either in cells or when applied directly as a purified peptide in inside-out patch recordings. Furthermore, using a cysteine cross-linking approach, we showed that relief of inhibition following cleavage requires dissociation of the C terminus from the channel pore. Collectively, these data suggest a mechanism of hPANX1 channel regulation whereby the intact, pore-associated C terminus inhibits the full-length hPANX1 channel and a remarkably well placed caspase cleavage site allows effective removal of key inhibitory C-terminal determinants to activate hPANX1.

Authors
Sandilos, JK; Chiu, Y-H; Chekeni, FB; Armstrong, AJ; Walk, SF; Ravichandran, KS; Bayliss, DA
MLA Citation
Sandilos, JK, Chiu, Y-H, Chekeni, FB, Armstrong, AJ, Walk, SF, Ravichandran, KS, and Bayliss, DA. "Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C-terminal autoinhibitory region." The Journal of Biological Chemistry 287.14 (March 2012): 11303-11311.
PMID
22311983
Source
epmc
Published In
The Journal of Biological Chemistry
Volume
287
Issue
14
Publish Date
2012
Start Page
11303
End Page
11311
DOI
10.1074/jbc.M111.323378

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. METHODS: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. RESULTS: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). CONCLUSIONS: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Authors
Armstrong, AJ; Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ
MLA Citation
Armstrong, AJ, Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, and George, DJ. "Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies." J Clin Oncol 30.5_suppl (February 10, 2012): 435-.
PMID
28143127
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
435
DOI
10.1200/jco.2012.30.5_suppl.435

Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC).

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Leopold, LH; Galsky, MD; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Leopold, LH, Galsky, MD, and Sonpavde, G. "Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC)." JOURNAL OF CLINICAL ONCOLOGY 30.5 (February 10, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5
Publish Date
2012
DOI
10.1200/jco.2012.30.5_suppl.204

A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy.

Authors
Hussain, M; Rathkopf, DE; Liu, G; Armstrong, AJ; Kelly, WK; Ferrari, AC; Hainsworth, JD; Yang, L; Schwartz, JD; Higano, CS
MLA Citation
Hussain, M, Rathkopf, DE, Liu, G, Armstrong, AJ, Kelly, WK, Ferrari, AC, Hainsworth, JD, Yang, L, Schwartz, JD, and Higano, CS. "A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy." JOURNAL OF CLINICAL ONCOLOGY 30.5 (February 10, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5
Publish Date
2012
DOI
10.1200/jco.2012.30.5_suppl.97

Long term safety and efficacy in a randomized multicenter international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer

Authors
Armstrong, AJ; Gingrich, JR; Haggman, M; Stadler, WM; Damber, JE; Belkoff, L; Clark, R; Brosman, S; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Gingrich, JR, Haggman, M, Stadler, WM, Damber, JE, Belkoff, L, Clark, R, Brosman, S, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Long term safety and efficacy in a randomized multicenter international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer." European Urology Supplements 11.1 (February 1, 2012): E126-U515.
Source
wos
Published In
European Urology Supplements
Volume
11
Issue
1
Publish Date
2012
Start Page
E126
End Page
U515

Long term safety and efficacy in a randomized multicenter international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer

Authors
Armstrong, AJ; Gingrich, JR; Haggman, M; Stadler, WM; Damber, JE; Belkoff, L; Clark, R; Brosman, S; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Gingrich, JR, Haggman, M, Stadler, WM, Damber, JE, Belkoff, L, Clark, R, Brosman, S, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Long term safety and efficacy in a randomized multicenter international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer." European Urology Supplements 11.1 (February 1, 2012): E126-U515.
Source
wos
Published In
European Urology Supplements
Volume
11
Issue
1
Publish Date
2012
Start Page
E126
End Page
U515

A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy.

97 Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis and insulin-like growth factor (IGF-IR)-mediated signaling contribute to mCRPC growth. CIX and RAM are fully human IgG1 human monoclonal antibodies targeting IGF-IR and VEGF receptor-2 (VEGFR-2) respectively. We investigated the safety and efficacy of CIX or RAM in combination with M + P in mCRPC pts with PD on DCT.Eligible pts had mCRPC and PD during/within 120 days of DCT, ECOG PS 0-2, PSA ≥ 2 ng/mL, and adequate organ function. All pts received M 12 mg/m2 IV every 3 weeks (w) + P 5 mg PO BID for up to 12 cycles and were randomized to either CIX 6 mg/kg or RAM 6 mg/kg IV q w. Tumor assessments were after the first 3 cycles and then q6w. Primary endpoint was composite progression-free survival (cPFS: either RECIST PD, bone scan PD or new skeletal events). Other endpoints included safety, response and overall survival (OS). Sample size was based on a targeted 50% increase in median (mdn) cPFS from 2.6 months (m) to 3.9 m.132 pts were treated; 66 each to CIX or RAM. Mdn age and baseline PSA was 65 yr and 129 ng/mL for pts treated with CIX and 68 yr and 111 ng/mL for RAM. Involvement of sites other than bone was CIX: 79% and RAM: 70%. The most frequent Grade ≥3 related adverse events for CIX/M/P: fatigue 17%, leukopenia 12%, and neutropenia 8%, and for RAM/M/P: leukopenia 8%, neutropenia 8% and hypertension 8%. Left ventricular dysfunction/CHF: 12% for CIX (0% G3) and 23% for RAM (8% G3). Mdn number of Rx cycles were 5 for CIX and 6 for RAM. Mdn follow-up was 22.7 m for CIX and 21.8 m for RAM. PSA response was 18.4% (8.8-32% 95% CI) on CIX and 22.0% (11.5-36% 95% CI) on RAM. Mdn cPFS and OS were 4.1 m (3.0-5.6 m 95% CI) and 10.8 m (6.5-13.0 m 95% CI) for CIX and 6.7 m (4.5-8.3 m 95% CI) and 13.0 m (9.5-16.0 m 95% CI) for RAM.CIX/M/P and RAM/M/P were reasonably tolerated and achieved the primary endpoint. Preliminary cPFS and OS of RAM/M/P appear encouraging; sustained disease control was observed in pts on both rx arms. Correlation of serum markers of IGF and VEGF activity with clinical endpoints is planned.

Authors
Hussain, M; Rathkopf, DE; Liu, G; Armstrong, AJ; Kelly, WK; Ferrari, AC; Hainsworth, JD; Yang, L; Schwartz, JD; Higano, CS
MLA Citation
Hussain, M, Rathkopf, DE, Liu, G, Armstrong, AJ, Kelly, WK, Ferrari, AC, Hainsworth, JD, Yang, L, Schwartz, JD, and Higano, CS. "A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 97-.
PMID
27968283
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
97

Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC).

204 Background: The efficacy of docetaxel following exposure to androgen synthesis inhibitors such as KC or abiraterone acetate (AA) is unknown. Given the emerging use of pre-docetaxel AA and docetaxel's inhibition of androgen signaling, we retrospectively evaluated the efficacy of every 3 week docetaxel with prednisone (DP) in mCRPC previously exposed to KC as compared to KC-naïve patients.A randomized phase II trial of men with mCRPC treated with DP+AT-101 (bcl-2 inhibitor) vs. DP+placebo was analyzed (stratified for pain and performance status). Both arms were combined for analysis as no significant differences were seen. Overall survival [OS], progression-free survival [PFS], objective response [ORR], pain and PSA response rates were estimated with and without prior KC.Of 220 evaluable men, 40 (18.2%) received prior KC (median duration=2.0 months, maximum=31.1 months). These 40 men had less visceral disease (15% vs 28%), more prior radiotherapy (70% vs 51%), and increased prior radiological (38% vs 21%) or bone scan progression (55% vs 41%). Efficacy outcomes were not statistically different (table). After adjusting for baseline stratum and treatment group, prior KC did not appear to significantly change OS with DP-based therapy (HR 1.34, 95%CI: 0.86-2.09, p=0.20).Similar outcomes were observed in mCRPC treated with DP-based therapy with or without prior KC. Given the marginally inferior survival with prior KC, evaluation of docetaxel outcomes following AA is of clinical importance, given its more potent CYP17 inhibition. [Table: see text].

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Leopold, LH; Galsky, MD; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Leopold, LH, Galsky, MD, and Sonpavde, G. "Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 204-.
PMID
27967949
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
204

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting.We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized.21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2).Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Authors
Armstrong, AJ; Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ
MLA Citation
Armstrong, AJ, Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, and George, DJ. "Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 435-.
PMID
27968068
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
435

A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy.

97 Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis and insulin-like growth factor (IGF-IR)-mediated signaling contribute to mCRPC growth. CIX and RAM are fully human IgG1 human monoclonal antibodies targeting IGF-IR and VEGF receptor-2 (VEGFR-2) respectively. We investigated the safety and efficacy of CIX or RAM in combination with M + P in mCRPC pts with PD on DCT.Eligible pts had mCRPC and PD during/within 120 days of DCT, ECOG PS 0-2, PSA ≥ 2 ng/mL, and adequate organ function. All pts received M 12 mg/m(2) IV every 3 weeks (w) + P 5 mg PO BID for up to 12 cycles and were randomized to either CIX 6 mg/kg or RAM 6 mg/kg IV q w. Tumor assessments were after the first 3 cycles and then q6w. Primary endpoint was composite progression-free survival (cPFS: either RECIST PD, bone scan PD or new skeletal events). Other endpoints included safety, response and overall survival (OS). Sample size was based on a targeted 50% increase in median (mdn) cPFS from 2.6 months (m) to 3.9 m.132 pts were treated; 66 each to CIX or RAM. Mdn age and baseline PSA was 65 yr and 129 ng/mL for pts treated with CIX and 68 yr and 111 ng/mL for RAM. Involvement of sites other than bone was CIX: 79% and RAM: 70%. The most frequent Grade ≥3 related adverse events for CIX/M/P: fatigue 17%, leukopenia 12%, and neutropenia 8%, and for RAM/M/P: leukopenia 8%, neutropenia 8% and hypertension 8%. Left ventricular dysfunction/CHF: 12% for CIX (0% G3) and 23% for RAM (8% G3). Mdn number of Rx cycles were 5 for CIX and 6 for RAM. Mdn follow-up was 22.7 m for CIX and 21.8 m for RAM. PSA response was 18.4% (8.8-32% 95% CI) on CIX and 22.0% (11.5-36% 95% CI) on RAM. Mdn cPFS and OS were 4.1 m (3.0-5.6 m 95% CI) and 10.8 m (6.5-13.0 m 95% CI) for CIX and 6.7 m (4.5-8.3 m 95% CI) and 13.0 m (9.5-16.0 m 95% CI) for RAM.CIX/M/P and RAM/M/P were reasonably tolerated and achieved the primary endpoint. Preliminary cPFS and OS of RAM/M/P appear encouraging; sustained disease control was observed in pts on both rx arms. Correlation of serum markers of IGF and VEGF activity with clinical endpoints is planned.

Authors
Hussain, M; Rathkopf, DE; Liu, G; Armstrong, AJ; Kelly, WK; Ferrari, AC; Hainsworth, JD; Yang, L; Schwartz, JD; Higano, CS
MLA Citation
Hussain, M, Rathkopf, DE, Liu, G, Armstrong, AJ, Kelly, WK, Ferrari, AC, Hainsworth, JD, Yang, L, Schwartz, JD, and Higano, CS. "A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC-1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 97-.
PMID
28143342
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
97

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting.We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized.21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2).Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Authors
Armstrong, AJ; Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ
MLA Citation
Armstrong, AJ, Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, and George, DJ. "Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 435-.
PMID
28143127
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
435

Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC).

204 Background: The efficacy of docetaxel following exposure to androgen synthesis inhibitors such as KC or abiraterone acetate (AA) is unknown. Given the emerging use of pre-docetaxel AA and docetaxel's inhibition of androgen signaling, we retrospectively evaluated the efficacy of every 3 week docetaxel with prednisone (DP) in mCRPC previously exposed to KC as compared to KC-naïve patients.A randomized phase II trial of men with mCRPC treated with DP+AT-101 (bcl-2 inhibitor) vs. DP+placebo was analyzed (stratified for pain and performance status). Both arms were combined for analysis as no significant differences were seen. Overall survival [OS], progression-free survival [PFS], objective response [ORR], pain and PSA response rates were estimated with and without prior KC.Of 220 evaluable men, 40 (18.2%) received prior KC (median duration=2.0 months, maximum=31.1 months). These 40 men had less visceral disease (15% vs 28%), more prior radiotherapy (70% vs 51%), and increased prior radiological (38% vs 21%) or bone scan progression (55% vs 41%). Efficacy outcomes were not statistically different (table). After adjusting for baseline stratum and treatment group, prior KC did not appear to significantly change OS with DP-based therapy (HR 1.34, 95%CI: 0.86-2.09, p=0.20).Similar outcomes were observed in mCRPC treated with DP-based therapy with or without prior KC. Given the marginally inferior survival with prior KC, evaluation of docetaxel outcomes following AA is of clinical importance, given its more potent CYP17 inhibition. [Table: see text].

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Leopold, LH; Galsky, MD; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Leopold, LH, Galsky, MD, and Sonpavde, G. "Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.5_suppl (February 2012): 204-.
PMID
28143010
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
5_suppl
Publish Date
2012
Start Page
204

Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer.

BACKGROUND: The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear. OBJECTIVE: A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles. MEASUREMENTS: Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion. RESULTS AND LIMITATIONS: The number of men receiving 10 cycles was similar (p=0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9-95.4%) and 74.6% (CI, 67.2-80.5%) in TAX-327, compared with 92.8% (CI, 85.5-96.5) and 63.4% (CI, 51.8-72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply. CONCLUSIONS: A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, L; Berry, WR; de Wit, R; Eisenberger, MA; Tannock, IF; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, L, Berry, WR, de Wit, R, Eisenberger, MA, Tannock, IF, and Sonpavde, G. "Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer." Eur Urol 61.2 (February 2012): 363-369.
PMID
21715086
Source
pubmed
Published In
Eur Urol
Volume
61
Issue
2
Publish Date
2012
Start Page
363
End Page
369
DOI
10.1016/j.eururo.2011.06.034

Prognostic, predictive, and surrogate factors for individualizing treatment for men with castration-resistant prostate cancer.

With the surge in therapeutic options for castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making, highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Here we discuss existing and potential prognostic, predictive, and surrogate biomarkers in CRPC.

Authors
Bitting, RL; Armstrong, AJ
MLA Citation
Bitting, RL, and Armstrong, AJ. "Prognostic, predictive, and surrogate factors for individualizing treatment for men with castration-resistant prostate cancer." American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting (January 2012): 292-297.
PMID
24451752
Source
epmc
Published In
American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Meeting
Publish Date
2012
Start Page
292
End Page
297
DOI
10.14694/edbook_am.2012.32.292

Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.

To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m(2) every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m(2) every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months.The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.

Authors
Araujo, JC; Mathew, P; Armstrong, AJ; Braud, EL; Posadas, E; Lonberg, M; Gallick, GE; Trudel, GC; Paliwal, P; Agrawal, S; Logothetis, CJ
MLA Citation
Araujo, JC, Mathew, P, Armstrong, AJ, Braud, EL, Posadas, E, Lonberg, M, Gallick, GE, Trudel, GC, Paliwal, P, Agrawal, S, and Logothetis, CJ. "Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study." Cancer 118.1 (January 2012): 63-71.
PMID
21976132
Source
epmc
Published In
Cancer
Volume
118
Issue
1
Publish Date
2012
Start Page
63
End Page
71
DOI
10.1002/cncr.26204

What to order from the prostate cancer treatment menu?

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to order from the prostate cancer treatment menu?." Oncology (Williston Park) 26.1 (January 2012): 84-88.
PMID
22393801
Source
pubmed
Published In
Oncology (Williston Park, N.Y.)
Volume
26
Issue
1
Publish Date
2012
Start Page
84
End Page
88

Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center.

PURPOSE: The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared to routine care. For patients with prostate cancer the goal is to provide evaluations by urologists, medical and radiation oncologists at a single visit. Although additional resources are required, this strategy may enhance the overall health care experience. We compared utilization determinants between a multidisciplinary and a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients. MATERIALS AND METHODS: We retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic and 1,318 urology prostate cancer clinic patients were examined with the rank sum and chi-square tests. Predictive factors for pursuing treatment at the university medical center were assessed using multivariate adjusted logistic regression. RESULTS: Compared to patients at the urology prostate cancer clinic those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles. CONCLUSIONS: A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution.

Authors
Stewart, SB; Bañez, LL; Robertson, CN; Freedland, SJ; Polascik, TJ; Xie, D; Koontz, BF; Vujaskovic, Z; Lee, WR; Armstrong, AJ; Febbo, PG; George, DJ; Moul, JW
MLA Citation
Stewart, SB, Bañez, LL, Robertson, CN, Freedland, SJ, Polascik, TJ, Xie, D, Koontz, BF, Vujaskovic, Z, Lee, WR, Armstrong, AJ, Febbo, PG, George, DJ, and Moul, JW. "Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center." J Urol 187.1 (January 2012): 103-108.
PMID
22088334
Source
pubmed
Published In
The Journal of Urology
Volume
187
Issue
1
Publish Date
2012
Start Page
103
End Page
108
DOI
10.1016/j.juro.2011.09.040

What to Order From the Prostate Cancer Treatment Menu? THE CRAWFORD/FLAIG ARTICLE REVIEWED

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to Order From the Prostate Cancer Treatment Menu? THE CRAWFORD/FLAIG ARTICLE REVIEWED." ONCOLOGY-NEW YORK 26.1 (January 2012): 84-+.
Source
wos-lite
Published In
Oncology (Williston Park, N.Y.)
Volume
26
Issue
1
Publish Date
2012
Start Page
84
End Page
+

Where does abiraterone fit into the metastatic prostate cancer treatment algorithm?

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Where does abiraterone fit into the metastatic prostate cancer treatment algorithm?." Community Oncology 9.8 (2012): 238-239.
Source
scival
Published In
Community Oncology
Volume
9
Issue
8
Publish Date
2012
Start Page
238
End Page
239
DOI
10.1016/j.cmonc.2012.07.006

Objective evaluation of bone metastases in prostate cancer: To what end?

Authors
Sonpavde, G; Armstrong, AJ
MLA Citation
Sonpavde, G, and Armstrong, AJ. "Objective evaluation of bone metastases in prostate cancer: To what end?." European Urology 62.1 (2012): 85-87.
PMID
22402111
Source
scival
Published In
European Urology
Volume
62
Issue
1
Publish Date
2012
Start Page
85
End Page
87
DOI
10.1016/j.eururo.2012.02.021

Reply to YiJun Shen and DingWei Ye's letter to the Editor re: Gregory R. Pond, Andrew J. Armstrong, Brian A. Wood, et al. Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol 2012;61:363-9

Authors
Sonpavde, G; Pond, GR; Armstrong, AJ
MLA Citation
Sonpavde, G, Pond, GR, and Armstrong, AJ. "Reply to YiJun Shen and DingWei Ye's letter to the Editor re: Gregory R. Pond, Andrew J. Armstrong, Brian A. Wood, et al. Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol 2012;61:363-9." European Urology 61.2 (2012): e4-e5.
Source
scival
Published In
European Urology
Volume
61
Issue
2
Publish Date
2012
Start Page
e4
End Page
e5
DOI
10.1016/j.eururo.2011.07.055

New and Emerging Therapies for Bone Metastases in Genitourinary Cancers

Context: Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality. Objective: The objective of this review is to discuss the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies. Evidence acquisition: We reviewed the relevant medical literature, with a particular emphasis on prospective randomized controlled trials. Much of the relevant clinical trial data focus on prostate cancer (PCa). We provide a nonsystematic review and our perspective on the available data. Evidence synthesis: Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for skeletal metastases often features a combination of disease-specific therapy and bone-targeted therapy. Some agents, such as the radiopharmaceutical radium-223, blur the line between those categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases. Zoledronic acid, a bisphosphonate, is approved for the prevention of skeletal events caused by solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that inactivates receptor activator of nuclear factor-κB ligand and is approved for the same indication. Beta-emitting radiopharmaceuticals can be effective for the palliation of pain caused by bone metastases, but their use is often limited by marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in select men with castration-resistant PCa metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET). Conclusions: Bone metastases cause considerable morbidity and mortality among patients with genitourinary malignancies. Optimal management requires consideration of bone-targeted therapy as well as disease-specific therapy. Further research is needed to optimize the use of existing agents and to define the therapeutic potential of novel targets. © 2012 European Association of Urology.

Authors
Saylor, PJ; Armstrong, AJ; Fizazi, K; Freedland, S; Saad, F; Smith, MR; Tombal, B; Pienta, K
MLA Citation
Saylor, PJ, Armstrong, AJ, Fizazi, K, Freedland, S, Saad, F, Smith, MR, Tombal, B, and Pienta, K. "New and Emerging Therapies for Bone Metastases in Genitourinary Cancers." European Urology (2012).
PMID
23201471
Source
scival
Published In
European Urology
Publish Date
2012
DOI
10.1016/j.eururo.2012.10.007

Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: Implications for prior therapy in clinical trials

Objectives: Abiraterone acetate (AA) is a CYP17 inhibitor of androgen synthesis approved for use following docetaxel for metastatic castration-resistant prostate cancer (mCRPC); evaluation in the pre-docetaxel setting is ongoing. Given that the reported efficacy of AA is lower following docetaxel vs. pre-docetaxel, the potential exists for cross resistance given docetaxel's partly androgen receptor targeting activity. The efficacy of docetaxel following ketoconazole (KC), a weaker and nonspecific inhibitor of CYP17, may provide some insights into this potential interaction. We retrospectively evaluated the efficacy of every 3-week docetaxel with prednisone (DP) in mCRPC previously exposed to KC compared to KC-naive patients. Materials and methods: A randomized phase II trial of men with mCRPC treated with DP + AT-101 (bcl-2 inhibitor) vs. DP plus placebo was analyzed. Both arms were combined for analysis as no significant differences were seen. Overall survival (OS), progression-free survival (PFS), objective response (ORR), pain, and prostate-specific antigen (PSA) response rates were estimated with and without prior KC. Cox proportional hazards regression models were used to estimate the effect of covariates on OS. Results: Of 220 evaluable men, 40 (18.2%) received prior KC. The median OS with DP-based therapy of KC-naive patients (18.3 months, 95% CI: 15.0, 24.5) and post-KC patients (17.0 months, 95% CI: 9.9, 20.4) was not statistically different (P = 0.20). After controlling for prognostic classifications, analyses demonstrated consistent trends for worsening of OS after KC, with (hazard ratios (HRs) 1.33-1.46. Similar unfavorable trends were observed for ORR, PSA declines, and PFS. Conclusions: In this hypothesis-generating analysis, patients treated with docetaxel-based chemotherapy following prior KC had numerically and consistently worse outcomes than patients not exposed to prior KC. Although the estimated differences did not attain statistical significance, evaluation of outcomes with docetaxel in particular, and all classes of novel and emerging agents following AA, is of clinical importance, given its more potent androgen synthesis inhibition compared with KC. Drug development should take into account the potential impact of previous therapy. © 2012 Elsevier Inc. All rights reserved.

Authors
Pond, GR; Armstrong, AJ; Galsky, MD; Wood, BA; Leopold, L; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Galsky, MD, Wood, BA, Leopold, L, and Sonpavde, G. "Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: Implications for prior therapy in clinical trials." Urologic Oncology: Seminars and Original Investigations (2012).
PMID
22552048
Source
scival
Published In
Urologic Oncology: Seminars and Original Investigations
Publish Date
2012
DOI
10.1016/j.urolonc.2012.02.008

What to order from the prostate cancer treatment menu?

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to order from the prostate cancer treatment menu?." Oncology 26.1 (2012).
Source
scival
Published In
Oncology (Williston Park, N.Y.)
Volume
26
Issue
1
Publish Date
2012

Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel-based chemotherapy

OBJECTIVE: • Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. PATIENTS AND METHODS: • A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively ( n = 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. RESULTS: • C-reactive protein was independently prognostic for OS and PFS ( P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. CONCLUSIONS: • Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted. © 2012 BJU International.

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Leopold, L; Galsky, MD; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Leopold, L, Galsky, MD, and Sonpavde, G. "Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel-based chemotherapy." BJU International 110.11 B (2012): E461-E468.
Source
scival
Published In
Bju International
Volume
110
Issue
11 B
Publish Date
2012
Start Page
E461
End Page
E468
DOI
10.1111/j.1464-410X.2012.11148.x

Epithelial-mesenchymal transition in cancer progression.

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Epithelial-mesenchymal transition in cancer progression." Clin Adv Hematol Oncol 9.12 (December 2011): 941-943.
PMID
22252665
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
9
Issue
12
Publish Date
2011
Start Page
941
End Page
943

The role of surrogate markers in the management of men with metastatic castration-resistant prostate cancer.

Over the past year, the treatment of metastatic castration-resistant prostate cancer (mCRPC) was dramatically altered with the introduction of several novel agents. One of these agents, the cancer immunotherapy sipuleucel-T, represents a major change in the treatment paradigm for patients with mCRPC. While immunotherapies such as sipuleucel-T are associated with a significant improvement in overall survival, many questions remain regarding their use. Specifically, there are questions as to which endpoints should be used to measure benefit with immunotherapy. Clinical trials of sipuleucel-T demonstrated that the traditional endpoints normally used in mCRPC trials, such as progression-free survival, are not good measures of response with immunotherapy. However, measurement of overall survival is difficult in the clinical trial setting. There is now a major interest in the identification of surrogate biomarkers of survival that could allow the benefit of novel agents to be more precisely determined. Many potential biomarkers have been identified, often from studies showing their prognostic potential. In this roundtable, experts discuss the role of biomarkers in measuring response to immunotherapy for men with mCRPC.

Authors
Armstrong, AJ; Ferrari, AC; Quinn, DI
MLA Citation
Armstrong, AJ, Ferrari, AC, and Quinn, DI. "The role of surrogate markers in the management of men with metastatic castration-resistant prostate cancer." Clin Adv Hematol Oncol 9.12 Suppl 28 (December 2011): 1-14. (Review)
PMID
22407145
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
9
Issue
12 Suppl 28
Publish Date
2011
Start Page
1
End Page
14

Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer.

PURPOSE: The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen. RESULTS: Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively (P < .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P = .0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus 3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters, were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis (4% v 0%) was more common in the TASQ arm. CONCLUSION: TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

Authors
Pili, R; Häggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Björk, A; Nordle, O; Forsberg, G; Carducci, MA; Armstrong, AJ
MLA Citation
Pili, R, Häggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Björk, A, Nordle, O, Forsberg, G, Carducci, MA, and Armstrong, AJ. "Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 29.30 (October 2011): 4022-4028.
PMID
21931019
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
30
Publish Date
2011
Start Page
4022
End Page
4028
DOI
10.1200/jco.2011.35.6295

The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy.

BACKGROUND: In men with metastatic castration-resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation. METHODS: Eligible patients for this analysis included those with World Health Organization (WHO)-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated by using the Kaplan-Meier method, and the prognostic relation of WHO-defined radiologic response with OS was performed by using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and at 2, 3, 4, and 6 months after baseline. RESULTS: Four hundred twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD, 24%) and 160 (38.8%) did not have a after-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. The authors found a significant association between ≥ 30% prostate-specific antigen (PSA) declines and radiologic response, with ≥ 30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD, and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ≥ 30% PSA decline (P = .009). CONCLUSIONS: In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS and appeared to complement PSA assessment.

Authors
Sonpavde, G; Pond, GR; Berry, WR; de Wit, R; Eisenberger, MA; Tannock, IF; Armstrong, AJ
MLA Citation
Sonpavde, G, Pond, GR, Berry, WR, de Wit, R, Eisenberger, MA, Tannock, IF, and Armstrong, AJ. "The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy." Cancer 117.17 (September 1, 2011): 3963-3971.
PMID
21365623
Source
pubmed
Published In
Cancer
Volume
117
Issue
17
Publish Date
2011
Start Page
3963
End Page
3971
DOI
10.1002/cncr.25982

Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer.

The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the past year, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel with prednisone and abiraterone acetate with prednisone), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are showing preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, which represents part 1 of a two-part series on metastatic CRPC, we will summarize the mechanisms of resistance to hormonal and chemotherapies and discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options following docetaxel administration, as well as prognostic factors in this post-docetaxel state. As docetaxel remains the standard initial systemic therapy for men with metastatic CRPC for both palliative and life-prolonging purposes, knowledge of these evolving standards will help to optimize delivery of care and long-term outcomes.

Authors
Antonarakis, ES; Armstrong, AJ
MLA Citation
Antonarakis, ES, and Armstrong, AJ. "Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer." Prostate Cancer Prostatic Dis 14.3 (September 2011): 192-205. (Review)
PMID
21577234
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Volume
14
Issue
3
Publish Date
2011
Start Page
192
End Page
205
DOI
10.1038/pcan.2011.23

Emerging therapeutic approaches in the management of metastatic castration-resistant prostate cancer.

Although treatment options for men with castration-resistant prostate cancer (CRPC) have improved with the recent and anticipated approvals of novel immunotherapeutic, hormonal, chemotherapeutic and bone-targeted agents, clinical benefit with these systemic therapies is transient and survival times remain unacceptably short. Thus, we devote the second section of this two-part review to discussing emerging therapeutic paradigms and research strategies that are entering phase II and III clinical testing for men with metastatic CRPC. We will discuss a range of emerging hormonal, immunomodulatory, antiangiogenic, epigenetic and cell survival pathway inhibitors in current clinical trials, with an emphasis on how these therapies may complement our existing treatment options.

Authors
Antonarakis, ES; Armstrong, AJ
MLA Citation
Antonarakis, ES, and Armstrong, AJ. "Emerging therapeutic approaches in the management of metastatic castration-resistant prostate cancer." Prostate Cancer Prostatic Dis 14.3 (September 2011): 206-218. (Review)
PMID
21577233
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Volume
14
Issue
3
Publish Date
2011
Start Page
206
End Page
218
DOI
10.1038/pcan.2011.24

Therapy for non-clear cell histologies in renal cancer.

The advent of targeted systemic therapies has significantly improved treatment options for patients with metastatic renal cell carcinoma (RCC). Multiple agents that inhibit angiogenesis cell growth and proliferation via the VEGF and mTOR (TORC1) pathways have been USFDA-approved for locally advanced or metastatic renal cell carcinoma in recent years although the majority of clinical trials have focused only on clear cell RCC. While clear cell RCC is the most common histologic subtype nearly 25% of RCC cases are histologic variants representing a diverse group of diseases with different prognoses underlying biology and molecular targets and therapies. This review will focus on the incidence clinical and pathologic features pathogenesis and treatment strategies of non-clear cell RCC in both the adjuvant and metastatic setting. These non-clear cell subtypes include papillary type 1 and type 2 chromophobe translocation carcinoma and collecting duct RCC. Controlled studies in these relatively rare subgroups are needed to inform upon clinical practice which is currently based on small series of uncontrolled studies. Ongoing clinical trials and areas of future research will be discussed.

Authors
Bitting, RL; Madden, J; Armstrong, AJ
MLA Citation
Bitting, RL, Madden, J, and Armstrong, AJ. "Therapy for non-clear cell histologies in renal cancer." Curr Clin Pharmacol 6.3 (August 2011): 169-180. (Review)
PMID
21861801
Source
pubmed
Published In
Current Clinical Pharmacology
Volume
6
Issue
3
Publish Date
2011
Start Page
169
End Page
180

Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

Authors
Armstrong, AJ; Marengo, MS; Oltean, S; Kemeny, G; Bitting, RL; Turnbull, JD; Herold, CI; Marcom, PK; George, DJ; Garcia-Blanco, MA
MLA Citation
Armstrong, AJ, Marengo, MS, Oltean, S, Kemeny, G, Bitting, RL, Turnbull, JD, Herold, CI, Marcom, PK, George, DJ, and Garcia-Blanco, MA. "Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers." Molecular Cancer Research : Mcr 9.8 (August 2011): 997-1007.
PMID
21665936
Source
epmc
Published In
Molecular Cancer Research : Mcr
Volume
9
Issue
8
Publish Date
2011
Start Page
997
End Page
1007
DOI
10.1158/1541-7786.MCR-10-0490

Investigator-initiated pilot study of sunitinib malate in patients with newly diagnosed prostate cancer prior to prostatectomy: A trial of the DoD/PCF Prostate Cancer Clinical Trials Consortium.

Authors
George, DJ; Halabi, S; Zurita, AJ; Creel, P; Mundy, K; Turnbull, JD; Yenser Wood, SE; Armstrong, AJ; Varley, RJ; Madden, J; Moul, JW
MLA Citation
George, DJ, Halabi, S, Zurita, AJ, Creel, P, Mundy, K, Turnbull, JD, Yenser Wood, SE, Armstrong, AJ, Varley, RJ, Madden, J, and Moul, JW. "Investigator-initiated pilot study of sunitinib malate in patients with newly diagnosed prostate cancer prior to prostatectomy: A trial of the DoD/PCF Prostate Cancer Clinical Trials Consortium." May 20, 2011.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
4664
End Page
4664
DOI
10.1200/jco.2011.29.15_suppl.4664

Ability of serum alkaline phosphatase (ALP) changes to complement PSA changes and predict survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel and prednisone (DP).

Authors
Fleming, MT; Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Matveev, VB; Burke, JM; Caton, JR; Sonpavde, G
MLA Citation
Fleming, MT, Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Matveev, VB, Burke, JM, Caton, JR, and Sonpavde, G. "Ability of serum alkaline phosphatase (ALP) changes to complement PSA changes and predict survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel and prednisone (DP)." Journal of Clinical Oncology 29.15_suppl (May 20, 2011): e15019-e15019.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
e15019
End Page
e15019
DOI
10.1200/jco.2011.29.15_suppl.e15019

Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC).

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Berry, WR; De Wit, R; Eisenberger, MA; Tannock, I; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Berry, WR, De Wit, R, Eisenberger, MA, Tannock, I, and Sonpavde, G. "Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 29.15_suppl (May 20, 2011): 4582-4582.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
4582
End Page
4582
DOI
10.1200/jco.2011.29.15_suppl.4582

Investigator-initiated pilot study of sunitinib malate in patients with newly diagnosed prostate cancer prior to prostatectomy: A trial of the DoD/PCF Prostate Cancer Clinical Trials Consortium.

4664 Background: Sunitinib malate (Sutent, Pfizer) is an oral multi-targeted tyrosine kinase inhibitor of VEGF/PDGF receptors that may function in part to inhibit prostate tumor growth via anti-angiogenic mechanisms.We conducted a multi-site study of sunitinib in patients with newly diagnosed, clinically localized prostate cancer prior to prostatectomy. After meeting eligibility requirements (intermediate to high risk, localized prostate cancer, adequate laboratory parameters, no prior treatment for prostate cancer), subjects received sunitinib 50mg PO for 28 days followed by a 1 week washout period followed by either radical retropubic or robot-assisted prostatectomy. Pathologic specimens (pretreatment biopsies and prostatectomy specimens) were evaluated for apoptotic (TUNEL) and proliferation (Ki-67) indices, microvessel density (MVD) and gene expression patterns.31 subjects were enrolled (median age 60 yrs; ECOG=0, biopsy Gleason 3+4=7). Data analysis is complete for 28 subjects. Most common toxicities (>30%) were diarrhea, fatigue, hypertension, mucositis, neutropenia, taste alterations, and thrombocytopenia. Most common grade 3-4 toxicities (> 5%) were hypertension, increased AST/ALT, and neutropenia. Median PSA decline was 13.6% (range -32% to 80%). Median change in Ki-67 was -34% (lower quartile -64% upper quartile +1.3%); median change in TUNEL was 4.5% (lower quartile -76%, upper quartile +286%); and median change in MVD (CD31) was +22% (lower quartile -23%, upper quartile +110%). Gene expression analysis is ongoing.Sunitinib given in the pre-prostastectomy setting appears safe and tolerable with a similar toxicity profile seen in patients with advanced cancer. Changes in proliferation and apoptosis suggest a treatment effect, while increases in MVD suggest a possible rebound effect off of sunitinib.

Authors
George, DJ; Halabi, S; Zurita, AJ; Creel, P; Mundy, K; Turnbull, JD; Yenser Wood, SE; Armstrong, AJ; Varley, RJ; Madden, J; Moul, JW
MLA Citation
George, DJ, Halabi, S, Zurita, AJ, Creel, P, Mundy, K, Turnbull, JD, Yenser Wood, SE, Armstrong, AJ, Varley, RJ, Madden, J, and Moul, JW. "Investigator-initiated pilot study of sunitinib malate in patients with newly diagnosed prostate cancer prior to prostatectomy: A trial of the DoD/PCF Prostate Cancer Clinical Trials Consortium." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 4664-.
PMID
28023877
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
4664

Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC).

4582 Background: The optimal number of cycles of 3-weekly DP therapy for mCRPC has not been ascertained. An exploratory analysis was conducted comparing results of 335 men on the DP arm of the TAX-327 study, which limited chemotherapy to 10 cycles, and a recently completed randomized clinical trial of 221 men allocated to either DP+AT-101 (bcl-2 inhibitor) versus DP+placebo, which allowed up to 17 cycles of DP.Patients who initiated cycle 10 of therapy without progression in both studies were included. Per protocol, men on the TAX-327 study received 1 additional cycle, while men on the AT-101 study received up to cycle 17. Men in both arms of the AT-101 study were combined for analysis, as no significant differences in outcomes were observed. Overall survival (OS) was estimated from the cycle 10 D infusion date, using the Kaplan-Meier method.The number of men receiving cycle 10 cycle was similar (Fisher's exact test p-value=0.60) between the two studies (166 or 49.6% in the TAX-327 study versus 99 or 44.8% in the AT-101 study), though of these men, death date information was more complete due to longer follow-up in TAX-327 (79.5% versus 34.4%). Six- and 12-month estimated survival from cycle 10 was 92.2% (95% CI: 86.9-95.4%) and 74.6% (CI: 67.2-80.5%) for TAX-327 patients, compared with 92.8% (CI: 85.5-96.5) and 63.4% (CI: 51.8-72.9%) for those on AT-101. Survival statistics were similar beyond cycle 10 within good, intermediate and poor risk groups. 38 (38.4%) men on the AT-101 study completed all 17 cycles. Of men on the AT-101 study, 24 and 13 had consistently declining PSA through cycles 13 and 17.A survival benefit was not detected with more than 10 cycles of DP chemotherapy in men with mCRPC in this hypothesis-generating exploratory analysis. A subset of men with mCRPC continue to have declines in PSA up to cycle 17 and thus may have ongoing benefit to continued chemotherapy administration. However, a randomized clinical trial is necessary to establish the optimal duration of therapy.

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Berry, WR; De Wit, R; Eisenberger, MA; Tannock, I; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Berry, WR, De Wit, R, Eisenberger, MA, Tannock, I, and Sonpavde, G. "Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 4582-.
PMID
28023307
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
4582

Ability of serum alkaline phosphatase (ALP) changes to complement PSA changes and predict survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel and prednisone (DP).

e15019 Background: PSA decline ≥30% and ≥50% within 90 days of starting chemotherapy are suboptimal surrogates for overall survival (OS) and only capture a proportion of total benefit. Changes in ALP were shown to complement PSA changes as prognostic factors for overall survival [OS] in men treated with chemotherapy in the TAX327 trial dataset. This analysis was performed to independently validate these findings in a different dataset.221 men recruited to a randomized phase II trial of DP+AT-101 (bcl-2 inhibitor) versus DP+placebo were studied. No significant differences in outcomes were observed; hence, both arms were combined for analysis. Changes in ALP and PSA prior to day 90 were measured and evaluated for prognostic ability to predict OS from day 90 using the Kaplan-Meir method and Cox proportional hazards regression. For inclusion, patients were required to have bony metastases at baseline, ALP ≥120 u/L and survival beyond day 90. ALP normalization was defined as an ALP of <120 and PSA response was defined as decline ≥30% from baseline within 90 days of randomization.100 men were eligible for analysis h ALP≥120 and 45 had normalization of ALP by day 90. OS from day 90 was significantly improved (HR: 0.38, 95% CI: 0.21-0.68) among those with normalization (1-year OS: 71.5%, 95% CI: 55.3-82.7) compared with those not having normalization (47.3%, 95% CI: 33.1-60.2). ALP normalization was independent of PSA response as a prognostic factor. 1-year OS for men with ALP normalization and with/without PSA-response was 76.9% / 62.5%, and for men without ALP normalization and with/without PSA-response was 56.6% / 30.0%. 29 men had increased ALP at day 90 from baseline and these men had significantly worse survival (9.7 months vs. 17.4 months) even after adjusting for PSA progression (hazard ratio:2.43; 95% CI: 1.48-4.00).ALP changes on DP based therapy complement PSA changes as prognostic factors associated with OS. Although not a surrogate for OS, ALP changes may be useful in estimating prognosis and facilitating treatment decisions in the setting of PSA flare or lack of PSA response to docetaxel.

Authors
Fleming, MT; Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Matveev, VB; Burke, JM; Caton, JR; Sonpavde, G
MLA Citation
Fleming, MT, Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Matveev, VB, Burke, JM, Caton, JR, and Sonpavde, G. "Ability of serum alkaline phosphatase (ALP) changes to complement PSA changes and predict survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel and prednisone (DP)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): e15019-.
PMID
28020589
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
e15019

Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC).

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Burke, JM; Caton, JR; Fleming, MT; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Burke, JM, Caton, JR, Fleming, MT, and Sonpavde, G. "Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 29.7_suppl (March 2011): 185-185.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
185
End Page
185
DOI
10.1200/jco.2011.29.7_suppl.185

Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy.

Authors
Sonpavde, G; Pond, GR; Berry, WR; De Wit, R; Eisenberger, MA; Tannock, I; Armstrong, AJ
MLA Citation
Sonpavde, G, Pond, GR, Berry, WR, De Wit, R, Eisenberger, MA, Tannock, I, and Armstrong, AJ. "Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy." Journal of Clinical Oncology 29.7_suppl (March 2011): 118-118.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
118
End Page
118
DOI
10.1200/jco.2011.29.7_suppl.118

Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups.

Authors
Armstrong, AJ; Haggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Haggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups." Journal of Clinical Oncology 29.7_suppl (March 2011): 126-126.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
126
End Page
126
DOI
10.1200/jco.2011.29.7_suppl.126

Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy.

118 Background: In men with metastatic castration resistant prostate cancer (CRPC),the association of measurable tumor responses with overall survival (OS) is unknown. We retrospectively evaluated the TAX327 phase III trial to study this relationship.Eligible patients for this analysis included those with WHO-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated using the Kaplan-Meier method and the prognostic relationship of WHO-defined radiologic response with OS was performed using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and 2, 3, 4 and 6 months after baseline.Four hundred and twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD,24%) and 160 (38.8%) did not have a post-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months), or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. We found a significant association between ≥30% PSA declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain-response and ≥30% PSA-decline (p=0.009).In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS, and appears to complement PSA assessment. [Table: see text].

Authors
Sonpavde, G; Pond, GR; Berry, WR; De Wit, R; Eisenberger, MA; Tannock, I; Armstrong, AJ
MLA Citation
Sonpavde, G, Pond, GR, Berry, WR, De Wit, R, Eisenberger, MA, Tannock, I, and Armstrong, AJ. "Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.7_suppl (March 2011): 118-.
PMID
27968667
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
118

Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups.

126 Background: Tasquinimod (TASQ) is an oral quinoline-3-carboxamide derivative that binds to S100A9 and displays anti-angiogenic and anti-tumor activity in prostate cancer (PC) models. In a randomized blinded phase II study, 206 (136 TASQ, 70 placebo [P]) men with metastatic castrate resistant (CRPC) were assigned to TASQ/P once-daily at an initial dose level of 0.25 mg/day escalating to 1.0 mg/day over 4 weeks. The primary endpoint to demonstrate an improvement in PCWG2 criteria-defined progression at 6 months was met and presented at ASCO 2010. This abstract provides an update on safety and efficacy including CRPC subgroups.Subgroups of patients based on baseline criteria were investigated for safety using NCI CTC v 3.0 criteria, PK and efficacy.201 (134 TASQ, 67 P) pts with a median age of 72.6 years received treatment and were evaluable for efficacy and safety. The updated analysis based on 5 additional PFS events confirmed an improved PFS of 7.6 vs. 3.3 months for pts on TASQ vs. P. Most progression events in both arms were radiological, but more pts progressed on bone scan in the P group. Radiographic PFS was 8.8 vs 4.4 months. Significant PFS improvements were observed in the PCWG2 risk groups with bone metastatic and visceral disease. TASQ treatment led to a transient increase in inflammatory lab markers such as CRP and fibrinogen, as well as asymptomatic increases in amylase/lipase. CRP increase was associated with adverse events (AEs) such as muscle and joint pain, while increased amylase was associated with a lower risk for gastrointestinal AEs. TASQ treatment was associated with anaemia, but did not affect CV risk factors such as hypertension or QTc prolongation, and the rate of composite cardiac events was acceptably low. Clearance of TASQ is decreased with age (1.4 % per year) and patients over 80 often required dose reduction due to increased exposure and toxicities.TASQ improved PFS in men with metastatic CRPC. Side effects are manageable and seem to correlate with laboratory markers. Individualized dosing based on tolerability is recommended and a phase III placebo-controlled study is being initiated. [Table: see text].

Authors
Armstrong, AJ; Haggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Haggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 29.7_suppl (March 2011): 126-null.
PMID
27968532
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
126

Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC).

185 Background: Threeprognosticrisk groups have been identified in men with mCRPC (good [GR]/intermediate [IR]/poor [PR]) based on 0-1, 2 or 3-4 factors (visceral disease, pain, anemia, bone scan progression). Prostate Cancer Working Group (PCWG)-2 defines clinical subtypes with visceral disease, bone metastases ± nodal metastases and nodal disease only. The prognostic ability of risk grouping or PCWG2 subtypes was evaluated in a large, independent phase II trial.A randomized phase IItrial of 221 men with mCRPC that received docetaxel-prednisone (DP) + AT-101 (Bcl-2 inhibitor) or DP + placebo was retrospectively analyzed using Cox regression and χ2 tests. Additional outcomes, tests and measures of discriminatory ability were assessed and will be presented. Patients from both groups were combined for analysis, as no significant differences in outcomes were observed.93, 81 and 38 men had GR, IR and PR disease. GR men were more likely than IR/PR men to be ECOG-PS 0 (48%, 27%, 21%) and had a lower median baseline PSA (63, 85, 193 ng/ml). Significant differences between risk groups were observed for progression-free survival (PFS, p=0.009) and overall survival (OS, p<0.001), while PCWG2 subtypes did not discriminate for these outcomes. Both risk groups and PCWG2 subtypes inconsistently predicted PSA declines (table).Prognostic risk groups significantly distinguished between outcomes in men with mCRPC receiving DP-based therapy, while PCWG2 subtypes did not. Risk groups may enhance stratification of patients in randomized trials and enable tailored drug development. Prognostic models that incorporate tumor molecular features may improve discriminatory ability. [Table: see text] [Table: see text].

Authors
Pond, GR; Armstrong, AJ; Wood, BA; Brookes, M; Leopold, LH; Burke, JM; Caton, JR; Fleming, MT; Sonpavde, G
MLA Citation
Pond, GR, Armstrong, AJ, Wood, BA, Brookes, M, Leopold, LH, Burke, JM, Caton, JR, Fleming, MT, and Sonpavde, G. "Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.7_suppl (March 2011): 185-.
PMID
27968482
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
7_suppl
Publish Date
2011
Start Page
185

Epithelial-mesenchymal transition in prostate cancer: providing new targets for therapy.

Authors
Armstrong, AJ; Freedland, SJ; Garcia Blanco, M
MLA Citation
Armstrong, AJ, Freedland, SJ, and Garcia Blanco, M. "Epithelial-mesenchymal transition in prostate cancer: providing new targets for therapy." Asian journal of andrology 13.2 (March 2011): 179-180. (Academic Article)
PMID
21383677
Source
manual
Published In
Asian journal of andrology
Volume
13
Issue
2
Publish Date
2011
Start Page
179
End Page
180
DOI
10.1038/aja.2010.169

Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?

Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with metastatic CRPC. With the United States Food and Drug Administration (US FDA) approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the landscape for management of men with metastatic CRPC has dramatically changed. In this review we will discuss the pivotal clinical trial data leading to these approvals, with particular focus on the unique indication for sipuleucel-T and the implications for optimal management and sequencing of treatment in this patient population.

Authors
Bitting, RL; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Armstrong, AJ, and George, DJ. "Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?." Clinical Medicine Insights. Oncology 5 (January 2011): 325-332.
PMID
22084621
Source
epmc
Published In
Clin Med Insights Oncol
Volume
5
Publish Date
2011
Start Page
325
End Page
332
DOI
10.4137/CMO.S5977

Clinical update: Epithelial-mesenchymal transition in cancer progression

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Clinical update: Epithelial-mesenchymal transition in cancer progression." Clinical Advances in Hematology and Oncology 9.12 (2011): 941-943.
Source
scival
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
9
Issue
12
Publish Date
2011
Start Page
941
End Page
943

Radiotherapy aids survival in clinically staged, node+ prostate Ca: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Radiotherapy aids survival in clinically staged, node+ prostate Ca: Commentary." Oncology Report JANUARY (2011): 25--.
Source
scival
Published In
Oncology Report
Issue
JANUARY
Publish Date
2011
Start Page
25-

RT mode has an impact on pelvic fracture risk in older patients: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "RT mode has an impact on pelvic fracture risk in older patients: Commentary." Oncology Report JANUARY (2011): 25--.
Source
scival
Published In
Oncology Report
Issue
JANUARY
Publish Date
2011
Start Page
25-

Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis.

Apoptotic cells release 'find-me' signals at the earliest stages of death to recruit phagocytes. The nucleotides ATP and UTP represent one class of find-me signals, but their mechanism of release is not known. Here, we identify the plasma membrane channel pannexin 1 (PANX1) as a mediator of find-me signal/nucleotide release from apoptotic cells. Pharmacological inhibition and siRNA-mediated knockdown of PANX1 led to decreased nucleotide release and monocyte recruitment by apoptotic cells. Conversely, PANX1 overexpression enhanced nucleotide release from apoptotic cells and phagocyte recruitment. Patch-clamp recordings showed that PANX1 was basally inactive, and that induction of PANX1 currents occurred only during apoptosis. Mechanistically, PANX1 itself was a target of effector caspases (caspases 3 and 7), and a specific caspase-cleavage site within PANX1 was essential for PANX1 function during apoptosis. Expression of truncated PANX1 (at the putative caspase cleavage site) resulted in a constitutively open channel. PANX1 was also important for the 'selective' plasma membrane permeability of early apoptotic cells to specific dyes. Collectively, these data identify PANX1 as a plasma membrane channel mediating the regulated release of find-me signals and selective plasma membrane permeability during apoptosis, and a new mechanism of PANX1 activation by caspases.

Authors
Chekeni, FB; Elliott, MR; Sandilos, JK; Walk, SF; Kinchen, JM; Lazarowski, ER; Armstrong, AJ; Penuela, S; Laird, DW; Salvesen, GS; Isakson, BE; Bayliss, DA; Ravichandran, KS
MLA Citation
Chekeni, FB, Elliott, MR, Sandilos, JK, Walk, SF, Kinchen, JM, Lazarowski, ER, Armstrong, AJ, Penuela, S, Laird, DW, Salvesen, GS, Isakson, BE, Bayliss, DA, and Ravichandran, KS. "Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis." Nature 467.7317 (October 2010): 863-867.
PMID
20944749
Source
epmc
Published In
Nature
Volume
467
Issue
7317
Publish Date
2010
Start Page
863
End Page
867
DOI
10.1038/nature09413

Optimizing the use of docetaxel in men with castration-resistant metastatic prostate cancer.

In 2009, castration-resistant metastatic prostate cancer continues to account for more deaths in US men than any other cancer apart from lung cancer. Although novel targeted molecular, hormonal and immunologic agents are accelerating in their development in this disease, docetaxel and prednisone remain the standard palliative regimen for the majority of men who have progressed despite hormonal therapies. Thus, understanding the practical and often subtle issues of docetaxel initiation, duration of therapy, cessation of therapy and treatment holidays is critical for the informed use of this US Food and Drug Administration-approved regimen. In this review we address these topics in light of prognostic and predictive factors to help guide the rational use of docetaxel chemotherapy in men with this aggressive disease.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "Optimizing the use of docetaxel in men with castration-resistant metastatic prostate cancer." Prostate Cancer Prostatic Dis 13.2 (June 2010): 108-116. (Review)
PMID
20066005
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Volume
13
Issue
2
Publish Date
2010
Start Page
108
End Page
116
DOI
10.1038/pcan.2009.62

A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.

Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy.Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum > or =7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy.Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood.At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed.

Authors
Armstrong, AJ; Netto, GJ; Rudek, MA; Halabi, S; Wood, DP; Creel, PA; Mundy, K; Davis, SL; Wang, T; Albadine, R; Schultz, L; Partin, AW; Jimeno, A; Fedor, H; Febbo, PG; George, DJ; Gurganus, R; De Marzo, AM; Carducci, MA
MLA Citation
Armstrong, AJ, Netto, GJ, Rudek, MA, Halabi, S, Wood, DP, Creel, PA, Mundy, K, Davis, SL, Wang, T, Albadine, R, Schultz, L, Partin, AW, Jimeno, A, Fedor, H, Febbo, PG, George, DJ, Gurganus, R, De Marzo, AM, and Carducci, MA. "A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 16.11 (June 2010): 3057-3066.
PMID
20501622
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
16
Issue
11
Publish Date
2010
Start Page
3057
End Page
3066
DOI
10.1158/1078-0432.CCR-10-0124

Impact of temsirolimus and anti-androgen therapy on circulating tumor cell (CTC) biology in men with castration-resistant metastatic prostate cancer (CRPC): A phase II study.

Authors
Armstrong, AJ; Kemeny, G; Turnbull, JD; Chao, C; Winters, C; Fesko, YA; Bradley, DA; Halabi, S; George, DJ; Garcia-Blanco, M
MLA Citation
Armstrong, AJ, Kemeny, G, Turnbull, JD, Chao, C, Winters, C, Fesko, YA, Bradley, DA, Halabi, S, George, DJ, and Garcia-Blanco, M. "Impact of temsirolimus and anti-androgen therapy on circulating tumor cell (CTC) biology in men with castration-resistant metastatic prostate cancer (CRPC): A phase II study." Journal of Clinical Oncology 28.15_suppl (May 20, 2010): TPS249-TPS249.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
TPS249
End Page
TPS249
DOI
10.1200/jco.2010.28.15_suppl.tps249

Serum lactate dehydrogenase (LDH) as a biomarker for survival with mTor inhibition in patients with metastatic renal cell carcinoma (RCC)

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Serum lactate dehydrogenase (LDH) as a biomarker for survival with mTor inhibition in patients with metastatic renal cell carcinoma (RCC)." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

A single arm phase Ib study of RAD001 and sunitinib in patients with advanced renal cell carcinoma (RCC).

Authors
Turnbull, JD; Armstrong, AJ; Morris, K; Wood, SEY; Voyles, S; Fesko, YA; George, DJ
MLA Citation
Turnbull, JD, Armstrong, AJ, Morris, K, Wood, SEY, Voyles, S, Fesko, YA, and George, DJ. "A single arm phase Ib study of RAD001 and sunitinib in patients with advanced renal cell carcinoma (RCC)." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Use of changes in serum alkaline phosphatase to predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy: A retrospective analysis of the TAX327 trial.

Authors
Pond, GR; Sonpavde, G; Berry, WR; De Wit, R; Armstrong, AJ; Eisenberger, MA; Tannock, I
MLA Citation
Pond, GR, Sonpavde, G, Berry, WR, De Wit, R, Armstrong, AJ, Eisenberger, MA, and Tannock, I. "Use of changes in serum alkaline phosphatase to predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy: A retrospective analysis of the TAX327 trial." Journal of Clinical Oncology 28.15_suppl (May 20, 2010): 4637-4637.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
4637
End Page
4637
DOI
10.1200/jco.2010.28.15_suppl.4637

A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer (CRPC)

Authors
Pili, R; Haggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Bjork, A; Forsberg, G; Carducci, MA; Armstrong, AJ
MLA Citation
Pili, R, Haggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Bjork, A, Forsberg, G, Carducci, MA, and Armstrong, AJ. "A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naive patients with metastatic castrate-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 28.15 (May 20, 2010).
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Phase I/II study of TH-302 in combination with docetaxel in patients with solid tumors including NSCLC and castrate-resistant prostate cancer (CRPC).

Authors
Sankhala, KK; Chiorean, EG; Armstrong, AJ; Borad, MJ; Traynor, AM; Gadgeel, SM; Langmuir, VK; Eng, C; Kroll, S; Burris, H
MLA Citation
Sankhala, KK, Chiorean, EG, Armstrong, AJ, Borad, MJ, Traynor, AM, Gadgeel, SM, Langmuir, VK, Eng, C, Kroll, S, and Burris, H. "Phase I/II study of TH-302 in combination with docetaxel in patients with solid tumors including NSCLC and castrate-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 28.15_suppl (May 20, 2010): e13527-e13527.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
e13527
End Page
e13527
DOI
10.1200/jco.2010.28.15_suppl.e13527

The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival.

AIMS OF THE STUDY: There are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a 30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC. METHODS: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n=656) and validated in M-treated men (n=333). RESULTS: Four independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0-1 factors, intermediate: 2 factors and poor: 3-4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p<0.0001); 30% PSAD in 78%, 66% and 58% of men (p<0.001); and measurable disease response in 19%, 9% and 5% of men (p=0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively. CONCLUSIONS: Risk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed.

Authors
Armstrong, AJ; Tannock, IF; de Wit, R; George, DJ; Eisenberger, M; Halabi, S
MLA Citation
Armstrong, AJ, Tannock, IF, de Wit, R, George, DJ, Eisenberger, M, and Halabi, S. "The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival." European Journal of Cancer (Oxford, England : 1990) 46.3 (February 2010): 517-525.
PMID
20005697
Source
epmc
Published In
European Journal of Cancer
Volume
46
Issue
3
Publish Date
2010
Start Page
517
End Page
525
DOI
10.1016/j.ejca.2009.11.007

ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation.

Cholesterol is a key component of cell membranes and is essential for cell growth and proliferation. How the accumulation of cellular cholesterol affects lymphocyte development and function is not well understood. We demonstrate that ATP-binding cassette transporter G1 (ABCG1) regulates cholesterol homeostasis in thymocytes and peripheral CD4 T cells. Our work is the first to describe a cell type in Abcg1-deficient mice with such a robust change in cholesterol content and the expression of cholesterol metabolism genes. Abcg1-deficient mice display increased thymocyte cellularity and enhanced proliferation of thymocytes and peripheral T lymphocytes in vivo. The absence of ABCG1 in CD4 T cells results in hyperproliferation in vitro, but only when cells are stimulated through the TCR. We hypothesize that cholesterol accumulation in Abcg1(-/-) T cells alters the plasma membrane structure, resulting in enhanced TCR signaling for proliferation. Supporting this idea, we demonstrate that B6 T cells pretreated with soluble cholesterol have a significant increase in proliferation. Cholesterol accumulation in Abcg1(-/-) CD4 T cells results in enhanced basal phosphorylation levels of ZAP70 and ERK1/2. Furthermore, inhibition of ERK phosphorylation in TCR-stimulated Abcg1(-/-) T cells rescues the hyperproliferative phenotype. We describe a novel mechanism by which cholesterol can alter signaling from the plasma membrane to affect downstream signaling pathways and proliferation. These results implicate ABCG1 as an important negative regulator of lymphocyte proliferation through the maintenance of cellular cholesterol homeostasis.

Authors
Armstrong, AJ; Gebre, AK; Parks, JS; Hedrick, CC
MLA Citation
Armstrong, AJ, Gebre, AK, Parks, JS, and Hedrick, CC. "ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation." J Immunol 184.1 (January 1, 2010): 173-183.
PMID
19949102
Source
pubmed
Published In
J Immunol
Volume
184
Issue
1
Publish Date
2010
Start Page
173
End Page
183
DOI
10.4049/jimmunol.0902372

Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer.

PURPOSE: We sought to evaluate predictors of overall survival following progression after systemic chemotherapy in men with metastatic castration-resistant prostate cancer. EXPERIMENTAL DESIGN: For our study population, we used the TAX327 multicenter randomized phase III trial comparing administration of docetaxel and prednisone every 3 weeks, weekly administration of docetaxel and prednisone, and administration of mitoxantrone and prednisone every 3 weeks. Progression was defined as the earliest of prostate-specific antigen (PSA), tumor, or pain progression. We analyzed predictors of postprogression survival according to both prechemotherapy and postchemotherapy variables with adjustment for potential confounders. RESULTS: Among 1,006 men, 640 had evaluable information on protocol-defined progression leading to further therapy. Median postprogression survival was 14.5 months. In the multivariable analysis, several pretreatment factors were associated with postprogression survival: pain, performance status, alkaline phosphatase, number of sites of metastatic disease, liver metastases, hemoglobin, PSA, and time since diagnosis. In addition, we found that the number of progression factors (PSA, pain, and tumor size), the duration of first-line chemotherapy, and whether progression occurred during chemotherapy independently predicted postprogression survival. We found evidence for the benefit of continuation of chemotherapy beyond progression only for men who had isolated worsening of pain. A nomogram was constructed and internally validated with a concordance index of 0.70. CONCLUSIONS: An internally validated model to predict postchemotherapy survival was developed. Evaluation of men in the postdocetaxel setting should consider the type of progression, duration of therapy, and known pretreatment prognostic factors. Definitions of progression in castration-resistant prostate cancer that include pain should also consider composite measures of tumor or PSA progression. External validation is planned.

Authors
Armstrong, AJ; Garrett-Mayer, E; de Wit, R; Tannock, I; Eisenberger, M
MLA Citation
Armstrong, AJ, Garrett-Mayer, E, de Wit, R, Tannock, I, and Eisenberger, M. "Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 16.1 (January 2010): 203-211.
PMID
20008841
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
16
Issue
1
Publish Date
2010
Start Page
203
End Page
211
DOI
10.1158/1078-0432.ccr-09-2514

Metastatic CRPC survival doesn't improve with added bevacizumab: Comment

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Metastatic CRPC survival doesn't improve with added bevacizumab: Comment." Oncology Report JULY-AUGUST (2010): 23--.
Source
scival
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2010
Start Page
23-

Denosumab prevents or stalls skeletal events in prostate cancer: Comment

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Denosumab prevents or stalls skeletal events in prostate cancer: Comment." Oncology Report JULY-AUGUST (2010): 23--.
Source
scival
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2010
Start Page
23-

Cabazitaxel prolongs survival in late metastatic CRPC: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Cabazitaxel prolongs survival in late metastatic CRPC: Commentary." Oncology Report MARCH-APRIL (2010): 22--.
Source
scival
Published In
Oncology Report
Issue
MARCH-APRIL
Publish Date
2010
Start Page
22-

IMPACT update: Survival benefit of sipuleucel-T is durable: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "IMPACT update: Survival benefit of sipuleucel-T is durable: Commentary." Oncology Report MARCH-APRIL (2010): 23--.
Source
scival
Published In
Oncology Report
Issue
MARCH-APRIL
Publish Date
2010
Start Page
23-

7028 Dasatinib and docetaxel combination treatment for patients with metastatic castration-resistant prostate cancer (CRPC): analysis of Study CA180–086

Authors
Araujo, J; Mathew, P; Armstrong, A; Braud, E; Posadas, E; Lonberg, M; Gallick, G; Trudel, G; Paliwal, P; Logothetis, C
MLA Citation
Araujo, J, Mathew, P, Armstrong, A, Braud, E, Posadas, E, Lonberg, M, Gallick, G, Trudel, G, Paliwal, P, and Logothetis, C. "7028 Dasatinib and docetaxel combination treatment for patients with metastatic castration-resistant prostate cancer (CRPC): analysis of Study CA180–086." September 2009.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
7
Issue
2
Publish Date
2009
Start Page
415
End Page
415
DOI
10.1016/S1359-6349(09)71406-5

Using surrogate biomarkers to predict clinical benefit in men with castration-resistant prostate cancer: an update and review of the literature.

Recurrent prostate cancer has a complex molecular etiology and a prolonged disease course. Although initially responsive to androgen ablation, many men eventually become castration resistant, develop skeletal metastases, and are palliatively treated with docetaxel-based chemotherapy, radiation therapy, bisphosphonates, and best supportive care. Given the modest success rates of the current standard of care, clinical trial enrollment is encouraged. Castration-resistant prostate cancer (CRPC) is a heterogeneous disease, both in clinical manifestations and outcomes, requiring an individualized approach to both patient care and trial design. Herein, we review surrogate markers of disease progression and treatment efficacy in advanced prostate cancer in light of recently published guidelines that have redefined eligibility, response criteria, and suitable endpoints in prostate cancer drug development. The guidelines have refined outcome measures to potentially better capture clinical benefit and the ability of novel targeted molecular and biologic agents to impact favorably on this disease. We consider prostate-specific antigen changes, circulating tumor cells, bone scan alterations, markers of bone metabolism (urinary N-telopeptide and bone-specific alkaline phosphatase), pain improvements, and progression-free survival. To illustrate the role and challenges of these potential biomarkers and endpoints in drug development, we discuss a class of novel molecularly targeted agents, the src kinase inhibitors. Given that there are currently no validated surrogate markers of overall survival for assessing early clinical benefit from systemic therapy in metastatic CRPC, incorporation of relevant biomarkers into all phases of clinical development is essential to accelerate drug development in this field.

Authors
Armstrong, AJ; Febbo, PG
MLA Citation
Armstrong, AJ, and Febbo, PG. "Using surrogate biomarkers to predict clinical benefit in men with castration-resistant prostate cancer: an update and review of the literature." The Oncologist 14.8 (August 14, 2009): 816-827. (Review)
PMID
19684076
Source
epmc
Published In
The Oncologist
Volume
14
Issue
8
Publish Date
2009
Start Page
816
End Page
827
DOI
10.1634/theoncologist.2009-0043

Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)

Authors
Araujo, J; Armstrong, AJ; Braud, EL; Posadas, E; Lonberg, M; Gallick, GE; Trudel, GC; Paliwal, P; Agrawal, S; Logothetis, CJ
MLA Citation
Araujo, J, Armstrong, AJ, Braud, EL, Posadas, E, Lonberg, M, Gallick, GE, Trudel, GC, Paliwal, P, Agrawal, S, and Logothetis, CJ. "Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens

Authors
Armstrong, AJ; Halabi, S; Tannock, IF; George, DJ; Dewit, R; Eisenberger, M
MLA Citation
Armstrong, AJ, Halabi, S, Tannock, IF, George, DJ, Dewit, R, and Eisenberger, M. "Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens.

5137 Background: Our aim was to develop and validate clinically applicable predictive factors for a >30% PSA decline 3 months following chemotherapy initiation, and to assess the performance of a risk-group based classification in predicting PSA declines and overall survival (OS) in men receiving chemotherapy for mCRPC.In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline at 3 months. Predictive factors for a >30% 3-month decline in PSA levels were identified using multivariate logistic regression in D treated men (n = 656) and validated in M treated men (n = 333). Risk factors were combined to form risk groups to predict PSA declines, OS, tumor, and pain responses. Prostate Cancer Working Group (PCWG2) disease states were evaluated for these outcomes in docetaxel treated men.In multivariate analysis, four independent risk factors predicted for absence of >30% decline in 3-month PSA: significant baseline pain (OR 0.63 p = 0.02), visceral metastases (OR 0.66, p = 0.03), anemia (hemoglobin <13 g/dl, OR 0.72 p = 0.07), and bone scan progression at baseline (OR 0.60 p = 0.009). Predictive accuracy was moderate with a concordance index (c-index) of 0.61. Risk groups (good, intermediate, poor) were developed with median OS of 25.7 (95% CI 23.3-28.6), 18.7 (17.3-19.7), and 12.8 (11.5-14.6) months, respectively (p < 0.0001), and >30% PSA decline in 78, 66, and 58 percent of men (p < 0.001). In the validation M cohort, similar trends for PSA declines and OS were noted across risk groups (OS 22.5, 16.0, 11.8 mo, p < 0.001). PCWG2 subtypes (node only, bone metastatic, and visceral disease), were also highly prognostic and predictive but did not predict OS as well as the TAX327 risk groups (c-index 0.56).Risk groups have been identified and internally validated that predict PSA decline and OS in men with mCRPC. This classification may facilitate evaluation of new regimens of systemic therapy that warrant definitive testing in comparison to docetaxel and prednisone in phase III trials. Prospective validation of these risk groups is needed. [Table: see text].

Authors
Armstrong, AJ; Halabi, S; Tannock, IF; George, DJ; DeWit, R; Eisenberger, M
MLA Citation
Armstrong, AJ, Halabi, S, Tannock, IF, George, DJ, DeWit, R, and Eisenberger, M. "Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 5137-.
PMID
27964425
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
5137

Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086).

5061 Background: Dasatinib, a potent inhibitor of SRC family kinases, inhibits in vitro prostate cancer cell proliferation and migration. Consistent with those findings are the clinical observations that osteoclast activity and bone turnover are downregulated in patients treated with dasatinib. We report promising preliminary results of dasatinib in combination with docetaxel (D) for treatment of metastatic castration-resistant prostate cancer (CRPC).Male pts with progressive CRPC and castrate levels of testosterone (≤50 ng/dL) requiring chemotherapy were enrolled. Escalating doses of dasatinib (50-120 mg QD) and D (60-75 mg/m2 Q 21 days) were evaluated (n = 16) followed by enrollment of 30 pts at the phase 2-selected dose (100 mg dasatinib QD + D at 75 mg/m2 Q 21 days). Continuation of bisphosphonates was permitted; anti-androgens were discontinued. Primary endpoint (Ph. 2) was to determine drug-drug interactions. Secondary endpoints were: changes in PSA, bone scans and tumor size, bone metabolism [urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP)] and PK.46 pts were treated with 28 pts still on therapy. Median treatment duration (n = 18, pts off study) was 4.2 months (0.13-9.63). Preliminary analysis showed no interaction between dasatinib and D. PSA response was seen in 13/32 (41%) pts, clinical benefit (PR + SD) for RECIST-evaluable pts was 21/21, [7 PR, 5 uPR and 4 SD (at ≥21 wks) and 5 SD at ≥6 wk)]. Of 31 pts with bone scans, 30 patients had a best response of either improved (32%) or stable (65%) at ≥6 weeks. For pts with measurable bone markers levels, 12/26 (46%) had a ≥35% decrease in uNTX and 17/24 (71%) had a decrease in BAP from baseline. 6 of 42 pts experienced ≥ grade 3 adverse events (AEs), including fatigue, myelosuppression and pleural effusion (n = 1). Most common grade 1/2 AEs were fatigue, dysgeusia, GI, and skin disorders.Dasatinib and D at doses up to 120 mg QD and 75 mg/m2 are safe with manageable toxicities and no drug-drug interactions. These data confirm the antitumor and antiosteoclast activity of dasatinib in combination with D and serve as the basis for the ongoing phase III study of this combination. [Table: see text].

Authors
Araujo, J; Armstrong, AJ; Braud, EL; Posadas, E; Lonberg, M; Gallick, GE; Trudel, GC; Paliwal, P; Agrawal, S; Logothetis, CJ
MLA Citation
Araujo, J, Armstrong, AJ, Braud, EL, Posadas, E, Lonberg, M, Gallick, GE, Trudel, GC, Paliwal, P, Agrawal, S, and Logothetis, CJ. "Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 5061-.
PMID
27962978
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
5061

The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer.

The purpose of this study was to evaluate the relationship of baseline body mass index (BMI) and serum testosterone level with prostate cancer outcomes in men with castration-resistant metastatic prostate cancer (CRPC). BMI and testosterone levels were evaluated for their ability to predict overall survival (OS) and prostate-specific antigen (PSA) declines in the TAX327 clinical trial, an international phase III randomized trial of one of the two schedules of docetaxel and prednisone compared with mitoxantrone and prednisone. In this study of 1006 men with CRPC, the median serum testosterone level was 14.5 ng per 100 ml (range 0-270), the median BMI was 27 kg m(-2) (range 15.7-46.5), and 26% of men were obese or morbidly obese (BMI>or=30). Obesity was associated with younger age, lower PSA and alkaline phosphatase levels, and higher performance status, primary Gleason sum, testosterone and hemoglobin compared to absence of obesity. In multivariate analysis, neither BMI, presence of obesity, nor baseline testosterone was significantly associated with OS or PSA declines. Higher testosterone levels among obese men suggest incomplete gonadal suppression with current therapies, but these differences may not be clinically relevant in men with CRPC. There was evidence of potential hemodilution of PSA and alkaline phosphatase levels in obese men.

Authors
Armstrong, AJ; Halabi, S; de Wit, R; Tannock, IF; Eisenberger, M
MLA Citation
Armstrong, AJ, Halabi, S, de Wit, R, Tannock, IF, and Eisenberger, M. "The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer." Prostate Cancer Prostatic Dis 12.1 (2009): 88-93.
PMID
18574490
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Volume
12
Issue
1
Publish Date
2009
Start Page
88
End Page
93
DOI
10.1038/pcan.2008.36

Bevacizumab increases toxicity, VTE in bladder cancer: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Bevacizumab increases toxicity, VTE in bladder cancer: Commentary." Oncology Report FALL (2009): 24--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2009
Start Page
24-

TroVax vaccine delivers mixed results in renal cell carcinoma: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "TroVax vaccine delivers mixed results in renal cell carcinoma: Commentary." Oncology Report WINT (2009): 26--.
Source
scival
Published In
Oncology Report
Issue
WINT
Publish Date
2009
Start Page
26-

Second vaccine shows improved survival in prostate cancer: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Second vaccine shows improved survival in prostate cancer: Commentary." Oncology Report FALL (2009): 25--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2009
Start Page
25-

A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer.

PURPOSE: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer. EXPERIMENTAL DESIGN: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity. RESULTS: Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy. CONCLUSIONS: The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.

Authors
Armstrong, AJ; Creel, P; Turnbull, J; Moore, C; Jaffe, TA; Haley, S; Petros, W; Yenser, S; Gockerman, JP; Sleep, D; Hurwitz, H; George, DJ
MLA Citation
Armstrong, AJ, Creel, P, Turnbull, J, Moore, C, Jaffe, TA, Haley, S, Petros, W, Yenser, S, Gockerman, JP, Sleep, D, Hurwitz, H, and George, DJ. "A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer." Clin Cancer Res 14.19 (October 1, 2008): 6270-6276.
PMID
18829508
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
14
Issue
19
Publish Date
2008
Start Page
6270
End Page
6276
DOI
10.1158/1078-0432.CCR-08-1085

Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Commentary." September 1, 2008.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
38

NCCN Task Force Report: mTOR inhibition in solid tumors.

The mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation, and angiogenesis. These pathways are frequently dysregulated in cancer, and therefore mTOR inhibition is a potentially important antitumor target. Commercially available mTOR inhibitors include rapamycin (i.e., sirolimus) and temsirolimus. Other agents under investigation include everolimus and deforolimus. mTOR inhibition has been studied in various solid tumors, including breast, gynecologic, gastrointestinal, prostate, lung, and head and neck cancers. Studies have focused on mTOR inhibition as a monotherapy or in combination with other drugs based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance. Temsirolimus is currently the only mTOR inhibitor that is specifically labeled for treatment of solid tumors. However, preclinical studies and early-phase trials are rapidly evolving. Additionally, research is further defining the complicated mTOR pathways and how they may be disordered in specific malignancies. To address these issues, NCCN convened a task force to review the underlying physiology of mTOR and related cellular pathways, and to review the current status of research of mTOR inhibition in solid tumors.

Authors
Figlin, RA; Brown, E; Armstrong, AJ; Akerley, W; Benson, AB; Burstein, HJ; Ettinger, DS; Febbo, PG; Fury, MG; Hudes, GR; Kies, MS; Kwak, EL; Morgan, RJ; Mortimer, J; Reckamp, K; Venook, AP; Worden, F; Yen, Y
MLA Citation
Figlin, RA, Brown, E, Armstrong, AJ, Akerley, W, Benson, AB, Burstein, HJ, Ettinger, DS, Febbo, PG, Fury, MG, Hudes, GR, Kies, MS, Kwak, EL, Morgan, RJ, Mortimer, J, Reckamp, K, Venook, AP, Worden, F, and Yen, Y. "NCCN Task Force Report: mTOR inhibition in solid tumors." J Natl Compr Canc Netw 6 Suppl 5 (September 2008): S1-20. (Review)
PMID
18926092
Source
pubmed
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
6 Suppl 5
Publish Date
2008
Start Page
S1
End Page
20

New drug development in metastatic prostate cancer.

In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify patient populations that may derive a greater benefit from these molecular agents.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "New drug development in metastatic prostate cancer." Urol Oncol 26.4 (July 2008): 430-437. (Review)
PMID
18593623
Source
pubmed
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
26
Issue
4
Publish Date
2008
Start Page
430
End Page
437
DOI
10.1016/j.urolonc.2007.11.006

A phase II trial of lapatinib in hormone refractory prostate cancer

Authors
Whang, YE; Moore, CN; Armstrong, AJ; Rathmell, WK; Godley, PA; Crane, JM; Grigson, GI; Morris, K; Watkins, CP; George, DJ
MLA Citation
Whang, YE, Moore, CN, Armstrong, AJ, Rathmell, WK, Godley, PA, Crane, JM, Grigson, GI, Morris, K, Watkins, CP, and George, DJ. "A phase II trial of lapatinib in hormone refractory prostate cancer." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer

Authors
Armstrong, AJ; Halabi, S; Tannock, IF; Ronald, D; Eisenberger, MA
MLA Citation
Armstrong, AJ, Halabi, S, Tannock, IF, Ronald, D, and Eisenberger, MA. "The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008
DOI
10.1200/jco.2008.26.15_suppl.5074

Re: Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens.

Authors
Armstrong, AJ; Garrett-Mayer, EL; Eisenberger, M
MLA Citation
Armstrong, AJ, Garrett-Mayer, EL, and Eisenberger, M. "Re: Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens." J Natl Cancer Inst 100.9 (May 7, 2008): 681-682. (Letter)
PMID
18445824
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
100
Issue
9
Publish Date
2008
Start Page
681
End Page
682
DOI
10.1093/jnci/djn104

Clinical endpoints for drug development in prostate cancer.

PURPOSE OF REVIEW: Overall survival remains the benchmark in phase III settings of novel agents in castration-resistant metastatic prostate cancer. This review highlights many of the current potential early measures of response and clinical benefit that are worthy of future study and validation in this disease. RECENT FINDINGS: The clinical evaluation of novel agents in advanced prostate cancer remains challenging for several reasons. Men with metastatic prostate cancer often have bone-only disease in which formal radiologic response and progression criteria may not apply. Declines in serum prostate-specific antigen levels may be modest surrogates of response to cytotoxic agents such as docetaxel, but have not been validated for agents with novel mechanisms of action, such as antiangiogenic, immunologic, or cytostatic drugs. Novel radiologic imaging techniques such as PET scans are not yet validated for use in monitoring or staging advanced prostate cancer. Measures of delay, control, and palliation of metastatic disease such as pain response, time to progression and progression-free survival, while appealing endpoints that may highlight the clinical benefit of novel agents, have been difficult to define rigorously and have not yet demonstrated adequate surrogacy for overall survival. SUMMARY: The measures of response highlighted in this review, if validated, may improve the current evaluation of novel agents in phase II settings and the potential accelerated approval of these agents.

Authors
Ramiah, V; George, DJ; Armstrong, AJ
MLA Citation
Ramiah, V, George, DJ, and Armstrong, AJ. "Clinical endpoints for drug development in prostate cancer." Curr Opin Urol 18.3 (May 2008): 303-308. (Review)
PMID
18382240
Source
pubmed
Published In
Current Opinion in Urology
Volume
18
Issue
3
Publish Date
2008
Start Page
303
End Page
308
DOI
10.1097/MOU.0b013e3282fb7807

Chemotherapy for advanced prostate cancer

© 2008 Informa UK Ltd. Introduction Prostate cancer will result in approximately 30,000 annual deaths in men in the United States in 2005 and is the second leading cause of cancer deaths in men after lung cancer.1,2 While the death rate from prostate cancer has been declining due to a number of factors such as earlier diagnosis and effective, less morbid local treatment options, approximately 6% of men will present with distant metastases and approximately 40% to 60% will relapse following local treatments.2-4 In general, androgen suppression leads to the response and stabilization of metastatic hormone-sensitive disease for approximately 18 to 24 months with a historic median survival from the time of diagnosis of metastases ranging from 24 to 30 months.5,6 A recent update of select patients from the Pound database from Johns Hopkins has demonstrated a median survival from development of metastases to death of 6.5 years.7 Prostate-specific antigen (PSA) doubling time at relapse following radical prostatectomy, time to recurrence, and original Gleason score were predictive of metastasis-free survival, illustrating the heterogeneity of this disease.7 However, eventually these patients will develop progressive hormone-refractory metastatic prostate cancer and these patients have a median survival of approximately 12 to 18 months.8-11 The concept that hormone-refractory metastatic prostate cancer is a chemo-resistant disease has been challenged by recent clinical trials. The use of surrogate outcomes such as PSA response has led to the more rapid identification of novel agents with activity in hormone-refractory metastatic prostate cancer (HRPC). Docetaxel (Taxotere), a taxoid with a more manageable benefit-to-toxicity ratio than historic cytotoxic agents used in prostate cancer, has demonstrated a clinical benefit and overall survival advantage in recent multi-institutional trials. Further refinements of the definitions of hormone independence, quality-of-life outcomes, and surrogate markers of response have led to improved standardization across clinical trials that allow for head to head comparisons of active agents.12,13 The earlier detection of biochemical recurrence and asymptomatic metastatic disease with the use of serum PSA measurements and improved imaging techniques may also translate into the earlier initiation of therapy before disease burden and pain become overwhelming factors. While hormone-refractory metastatic prostate cancer remains an incurable disease, chemotherapy has come to play a role in prolonging patient survival with meaningful quality-of-life endpoints and has generated optimism about progress among both clinicians and patients.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "Chemotherapy for advanced prostate cancer." Treatment Methods for Early and Advanced Prostate Cancer. January 1, 2008. 327-339.
Source
scopus
Publish Date
2008
Start Page
327
End Page
339

Cell signaling modifiers in prostate cancer.

Despite advances in the treatment of hormone-refractory prostate cancer (HRPC) with docetaxel chemotherapy as evidenced by the TAX 327 and SWOG 99-16 trials, therapeutic options remain limited in patients with cancer that progresses while they are receiving hormone manipulation and chemotherapy. Targeted therapies against receptor tyrosine kinases of the ErbB family have shown some promise in the treatment of HRPC; however, patient characteristics defining susceptibility to ErbB-targeted therapies remain unknown in HRPC and limits their efficacy in the clinic. Targeted inhibition of downstream pathways, namely mammalian target of rapamycin (mTOR) may prove to be important in the treatment of HRPC because of the prevalence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss, and it has been shown preclinically that mTOR inhibition reverses the phenotype of PTEN loss. Further investigation is necessary for the targeted inhibition of receptor tyrosine kinases and mTOR in HRPC. However, these classes of drugs may prove efficacious as tumoricidal agents or as chemo- and radiosensitizers.

Authors
Chen, FL; Armstrong, AJ; George, DJ
MLA Citation
Chen, FL, Armstrong, AJ, and George, DJ. "Cell signaling modifiers in prostate cancer." Cancer J 14.1 (January 2008): 40-45. (Review)
PMID
18303482
Source
pubmed
Published In
Cancer Journal (Sudbury, Mass.)
Volume
14
Issue
1
Publish Date
2008
Start Page
40
End Page
45
DOI
10.1097/PPO.0b013e318161d40f

Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Commentary." Oncology Report FALL (2008): 38--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
38-

Abiraterone acetate active in castration-resistant trials: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Abiraterone acetate active in castration-resistant trials: Commentary." Oncology Report FALL (2008): 39--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
39-

Thalidomide prolongs PFS following androgen failure: Commentary

Authors
Armstrong, AJ
MLA Citation
Armstrong, AJ. "Thalidomide prolongs PFS following androgen failure: Commentary." Oncology Report FALL (2008): 40--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
40-

A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis.

PURPOSE: To develop a prognostic model and nomogram using baseline clinical variables to predict death among men with metastatic hormone-refractory prostate cancer (HRPC). EXPERIMENTAL DESIGN: TAX327 was a clinical trial that randomized 1,006 men with metastatic HRPC to receive every three week or weekly docetaxel or mitoxantrone, each with prednisone. We developed a multivariate Cox model and nomogram to predict survival at 1, 2, and 5 years. RESULTS: Ten independent prognostic factors other than treatment group were identified in multivariate analysis: (a) presence of liver metastases [hazard ratio (HR), 1.66; P = 0.019], (b) number of metastatic sites (HR, 1.63 if > or =2 sites; P = 0.001), (c) clinically significant pain (HR, 1.48; P < 0.0001), (d) Karnofsky performance status (HR, 1.39 if < or =70; P = 0.016), (e) type of progression (HR, 1.37 for measurable disease progression and 1.29 for bone scan progression; P = 0.005 and 0.01, respectively), (f) pretreatment prostate-specific antigen (PSA) doubling time (HR, 1.19 if <55 days; P = 0.066), (g) PSA (HR, 1.17 per log rise; P < 0.0001), (h) tumor grade (HR, 1.18 for high grade; P = 0.069), (i) alkaline phosphatase (HR, 1.27 per log rise; P < 0.0001), and (j) hemoglobin (HR, 1.11 per unit decline; P = 0.004). A nomogram was developed based on this multivariate model and validated internally using bootstrap methods, with a concordance index of 0.69. CONCLUSIONS: This multivariate model identified several new independent prognostic factors in men with metastatic HRPC, including PSA doubling time, and led to the successful development of a clinically applicable nomogram. External prospective validation may support the wider use of this prognostic baseline model for men with HRPC treated with chemotherapy.

Authors
Armstrong, AJ; Garrett-Mayer, ES; Yang, Y-CO; de Wit, R; Tannock, IF; Eisenberger, M
MLA Citation
Armstrong, AJ, Garrett-Mayer, ES, Yang, Y-CO, de Wit, R, Tannock, IF, and Eisenberger, M. "A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 13.21 (November 2007): 6396-6403.
PMID
17975152
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
21
Publish Date
2007
Start Page
6396
End Page
6403
DOI
10.1158/1078-0432.ccr-07-1036

Satraplatin in the treatment of hormone-refractory metastatic prostate cancer.

Satraplatin is an orally bioavailable platinum chemotherapeutic agent under development for several cancer types, including hormone-refractory prostate cancer (HRPC). Satraplatin is being developed for the treatment of men with chemorefractory HRPC for several reasons: 1) relative ease of administration, 2) potential lack of cross-resistance with other platinum agents, 3) clinical benefits seen in early studies of HRPC, and 4) an unmet need in this patient population after docetaxel failure. As men who have progressed after docetaxel and prednisone have an expected median survival of approximately 12 months, there is great opportunity for improved palliation in this disease. Satraplatin may provide a palliative benefit for these men in terms of progression-free survival according to the most recent analyses of the phase III SPARC trial comparing satraplatin and prednisone to prednisone alone in the second-line setting for HRPC, and is currently under USFDA review for this indication. Whether satraplatin and prednisone offer an advantage over docetaxel retreatment or other cytotoxic agents in this setting is an unanswered question and worthy of study. Investigation of predictors of platinum sensitivity and the use of satraplatin in patients with neuroendocrine subsets of metastatic prostate cancer may be warranted given the advances in biomarker and genomic technology and the known sensitivity of small cell cancers to platinum agents. Further study of satraplatin alone or in combination with docetaxel or other molecular and chemotherapeutic agents seems warranted to improve on current outcomes.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "Satraplatin in the treatment of hormone-refractory metastatic prostate cancer." Ther Clin Risk Manag 3.5 (October 2007): 877-883.
PMID
18473011
Source
pubmed
Published In
Therapeutics and Clinical Risk Management
Volume
3
Issue
5
Publish Date
2007
Start Page
877
End Page
883

Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer.

PURPOSE: It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial. PATIENTS AND METHODS: In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate. RESULTS: A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival. CONCLUSION: In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.

Authors
Armstrong, AJ; Garrett-Mayer, E; Ou Yang, Y-C; Carducci, MA; Tannock, I; de Wit, R; Eisenberger, M
MLA Citation
Armstrong, AJ, Garrett-Mayer, E, Ou Yang, Y-C, Carducci, MA, Tannock, I, de Wit, R, and Eisenberger, M. "Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer." J Clin Oncol 25.25 (September 1, 2007): 3965-3970.
PMID
17761981
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
25
Publish Date
2007
Start Page
3965
End Page
3970
DOI
10.1200/JCO.2007.11.4769

Anti-angiogenic therapy in renal cell cancer.

Angiogenesis is an important hallmark of RCC, reflected in the natural history, Histology, genetics and now therapeutics of this disease. Clearly, the pro-angiogenic growth factor VEGF is a functional drug target in RCC and many strategies to inhibit this biology have shown clinical benefit. Multi-targeted TKI that inhibit VEGFRs have been approved by the FDA as standard treatment for advanced RCC. Pharmacodynamyc studies suggest that these agents and others also have anti-angiogenic effects. Currently, studies combining VEGFR-targeted strategies with other anti-angiogenic agents, including anti-VEGF antibodies, IFN or mTOR inhibitors, are underway. However, to what extent the clinical benefit of anti-angiogenic strategies in RCC can be built upon is unknown.

Authors
Srinivasan, R; Armstrong, AJ; Dahut, W; George, DJ
MLA Citation
Srinivasan, R, Armstrong, AJ, Dahut, W, and George, DJ. "Anti-angiogenic therapy in renal cell cancer." BJU Int 99.5 Pt B (May 2007): 1296-1300. (Review)
PMID
17441927
Source
pubmed
Published In
Bju International
Volume
99
Issue
5 Pt B
Publish Date
2007
Start Page
1296
End Page
1300
DOI
10.1111/j.1464-410X.2007.06834.x

Systemic strategies for prostate cancer.

Systemic therapy beyond hormonal therapy for advanced prostate cancer includes chemotherapy, antiangiogenic therapy, signal transduction inhibitors, immunomodulatory therapy, and other experimental therapeutics. This review will discuss the state of systemic therapy for advanced prostate cancer in 2007, with an emphasis on therapy in the neoadjuvant, adjuvant, and metastatic setting. As chemotherapy gains greater acceptance in the urologic oncology community for use in men with hormone-refractory disease, evaluating the role of systemic therapy in earlier disease states is essential given the success in other solid tumors for advancing cure rates. Current randomized phase III trials worldwide are addressing these questions in each disease state, and are anticipated to change the landscape of prostate cancer management for years to come. In this discussion, we will emphasize those agents that are currently being evaluated in phase II and III trials, with an emphasis on those trials that are likely to impact the standard of care in the near future. The collection of tumor or surrogate tissue is emphasized to define biomarkers that may predict for sensitivity to these systemic therapies.

Authors
Armstrong, AJ; Febbo, PG; George, DJ; Moul, J
MLA Citation
Armstrong, AJ, Febbo, PG, George, DJ, and Moul, J. "Systemic strategies for prostate cancer." Minerva Urol Nefrol 59.1 (March 2007): 11-25. (Review)
PMID
17431367
Source
pubmed
Published In
Minerva Urologica E Nefrologica = the Italian Journal of Urology and Nephrology
Volume
59
Issue
1
Publish Date
2007
Start Page
11
End Page
25

Current standard and investigational approaches to the management of hormone-refractory prostate cancer.

Prostate cancer is a common cause of death in men and remains incurable in the metastatic setting. In 2004, 2 landmark trials using docetaxel-based chemotherapy, TAX 327 and SWOG 99-16, showed a survival benefit for the first time in metastatic, hormone-refractory prostate cancer. Current research suggests that several distinct mechanisms of androgen-refractory disease may converge in patients with disease progression on androgen deprivation therapy. These findings have identified several potential targets for therapeutic intervention. Current standard and investigational treatment options for this disease are discussed, including chemotherapy and rapidly evolving therapies in phase II/III trials involving antiangiogenic therapies, signal transduction inhibitors, immunomodulatory agents, and nuclear receptor targets. In light of a growing array of treatment options and an increasingly chronic natural history, this review supports a multidisciplinary care approach to these patients, including medical oncologists, urologists, and radiation oncologists, to optimize survival and quality of life.

Authors
Mendiratta, P; Armstrong, AJ; George, DJ
MLA Citation
Mendiratta, P, Armstrong, AJ, and George, DJ. "Current standard and investigational approaches to the management of hormone-refractory prostate cancer." Rev Urol 9 Suppl 1 (2007): S9-S19.
PMID
17387372
Source
pubmed
Published In
Reviews in Urology
Volume
9 Suppl 1
Publish Date
2007
Start Page
S9
End Page
S19

In reply [12]

Authors
Armstrong, AJ; Garrett-Mayer, E; Eisenberger, M; Tannock, I; Wit, RD
MLA Citation
Armstrong, AJ, Garrett-Mayer, E, Eisenberger, M, Tannock, I, and Wit, RD. "In reply [12]." Journal of Clinical Oncology 25.35 (2007): 5674--.
Source
scival
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
35
Publish Date
2007
Start Page
5674-
DOI
10.1200/JCO.2007.14.5383

New drugs in prostate cancer.

PURPOSE OF REVIEW: The survival of hormone-refractory metastatic prostate cancer patients has improved with the use of docetaxel-based chemotherapy. The survival benefits, however, are modest suggesting that rationally designed therapeutic approaches are needed. We discuss recent developments in the therapeutic approach to advanced metastatic hormone-refractory prostate cancer, including molecularly targeted therapy, signal transduction inhibitors, stem-cell targeted therapy, anti-angiogenic compounds, vaccines and immunomodulating agents, differentiation agents, cytotoxics, and pro-apoptotic agents. RECENT FINDINGS: Over 200 compounds have entered clinical development for use in advanced prostate cancer, alone or in combination with cytotoxic agents such as docetaxel, or in other combinations. This article will review the results of emerging targets since the approval of docetaxel in 2004, concentrating on some of those compounds that, in our opinion, have the greatest potential and rationale for use. SUMMARY: The growing field of targeted molecular therapy of prostate cancer has opened up numerous opportunities for therapeutic impact. Knowledge of the molecular determinants of progression, relapse after local therapy, chemotherapeutic resistance, and hormone refractoriness remains essential in the rational design of clinical trials of these agents. Given the complexity, heterogeneity, and crosstalk of molecular pathways and the molecular lesions in prostate cancer, combination or sequential therapy may be a necessary step towards significant therapeutic progress. Novel translational clinical trial methodologies may assist in a more rapid identification of active compounds at biologically active doses for phase-III testing.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "New drugs in prostate cancer." Curr Opin Urol 16.3 (May 2006): 138-145. (Review)
PMID
16679849
Source
pubmed
Published In
Current Opinion in Urology
Volume
16
Issue
3
Publish Date
2006
Start Page
138
End Page
145
DOI
10.1097/01.mou.0000193390.69845.bb

Does gonadotropin-releasing-hormone agonist therapy for prostate cancer increase the risk of fracture?

Authors
Armstrong, AJ; Eisenberger, M
MLA Citation
Armstrong, AJ, and Eisenberger, M. "Does gonadotropin-releasing-hormone agonist therapy for prostate cancer increase the risk of fracture?." Nat Clin Pract Urol 3.5 (May 2006): 246-247.
PMID
16691232
Source
pubmed
Published In
Nature Clinical Practice. Urology
Volume
3
Issue
5
Publish Date
2006
Start Page
246
End Page
247
DOI
10.1038/ncpuro0462

Advanced prostate cancer: the future.

The demonstration of a survival benefit with docetaxel for the treatment of metastatic hormone refractory prostate cancer (HRPC) is an important step forward in advancing treatment options for advanced prostate cancer. While docetaxel-based therapy has demonstrated improvement in symptomatic and quality-of-life endpoints, certainly there is a pressing need for improvement in outcomes. A number of novel agents are in basic and clinical development for advanced prostate cancer, some of which are specific to mechanisms that may be important in the development and spread of prostate cancer. Novel approaches including novel cytotoxics, immunotherapy, PSMA targeted monoclonal antibodies are among the broad categories that will be discussed in this brief review.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "Advanced prostate cancer: the future." Can J Urol 12 Suppl 2 (June 2005): 42-47. (Review)
PMID
16018833
Source
pubmed
Published In
Canadian Journal of Urology
Volume
12 Suppl 2
Publish Date
2005
Start Page
42
End Page
47

Chemotherapy for advanced prostate cancer: results of new clinical trials and future studies.

Our understanding of the role of chemotherapy for advanced prostate cancer has improved considerably in 2004 with the publication of two large randomized phase III trials and the approval by the US Food and Drug Administration of docetaxel and prednisone for metastatic hormone-refractory disease. Although treatment is still considered palliative in nature, studies of chemotherapy for metastatic hormone-refractory prostate cancer (HRPC) have demonstrated improved overall survival compared with older regimens as well as clinically significant improvements in important endpoints, such as quality of life and time to progression. In particular, docetaxel has emerged as first-line therapy on an every-3-week schedule for metastatic HRPC, replacing mitoxantrone, as recently reported in the TAX327 trial. Docetaxel and estramustine combinations have the disadvantage of significant cardiovascular and gastrointestinal toxicity, and further use of estramustine is likely unwarranted as first-line therapy. Future trials examining novel biologic agents and combination therapies should use single-agent docetaxel as the reference standard. The role of chemotherapy for advanced disease in the neoadjuvant or adjuvant setting, in biochemically (PSA) relapsed patients, and as second-line therapy for relapsed disease, remains a subject of active clinical investigation.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "Chemotherapy for advanced prostate cancer: results of new clinical trials and future studies." Curr Oncol Rep 7.3 (May 2005): 220-227. (Review)
PMID
15847714
Source
pubmed
Published In
Current Oncology Reports
Volume
7
Issue
3
Publish Date
2005
Start Page
220
End Page
227

Novel therapeutic approaches to advanced prostate cancer.

Considerable progress in the treatment of advanced prostate cancer was made in 2004 with the approval by the US Food and Drug Administration of docetaxel for the treatment of metastatic hormone-refractory prostate cancer. The survival benefit with docetaxel and prednisone, however, has been modest, on the order of 2-3 months compared with mitoxantrone and prednisone. While docetaxel-based therapy has demonstrated improvement in symptomatic and quality-of-life endpoints, certainly there is a pressing need for improvement in outcomes. A number of novel agents are in basic and clinical development for advanced prostate cancer, some of which are specific to mechanisms that may be important in the development and spread of prostate cancer. Novel approaches including immunotherapy, antiangiogenic compounds, and cell growth and survival pathway inhibitors, as well as targeted cytotoxic compounds, are among the broad categories that will be discussed in this review. Clinical advances in meaningful endpoints such as survival and quality of life are eagerly awaited in large-scale trials of active and rationally designed agents.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "Novel therapeutic approaches to advanced prostate cancer." Clin Adv Hematol Oncol 3.4 (April 2005): 271-282. (Review)
PMID
16167000
Source
pubmed
Published In
Clinical Advances in Hematology & Oncology : H&O
Volume
3
Issue
4
Publish Date
2005
Start Page
271
End Page
282

Chemotherapy for advanced prostate cancer

© 2006 by Taylor & Francis Group, LLC. INTRODUCTION Prostate cancer will result in approximately 30,000 annual deaths in men in the United States in 2005 and is the second leading cause of cancer deaths in men after lung cancer.1,2 While the death rate from prostate cancer has been declining due to a number of factors such as earlier diagnosis and effective, less morbid local treatment options, approximately 6% of men will present with distant metastases and approximately 40% to 60% will relapse following local treatments.2-4 In general, androgen suppression leads to the response and stabilization of metastatic hormone-sensitive disease for approximately 18 to 24 months with a historic median survival from the time of diagnosis of metastases ranging from 24 to 30 months.5,6 A recent update of select patients from the Pound database from Johns Hopkins has demonstrated a median survival from development of metastases to death of 6.5 years.7 Prostate-specific antigen (PSA) doubling time at relapse following radical prostatectomy, time to recurrence, and original Gleason score were predictive of metastasis-free survival, illustrating the heterogeneity of this disease.7 However, eventually these patients will develop progressive hormone-refractory metastatic prostate cancer and these patients have a median survival of approximately 12 to 18 months.8-11 The concept that hormone-refractory metastatic prostate cancer is a chemo-resistant disease has been challenged by recent clinical trials. The use of surrogate outcomes such as PSA response has led to the more rapid identification of novel agents with activity in hormonerefractory metastatic prostate cancer (HRPC). Docetaxel (Taxotere), a taxoid with a more manageable benefit-totoxicity ratio than historic cytotoxic agents used in prostate cancer, has demonstrated a clinical benefit and overall survival advantage in recent multi-institutional trials. Further refinements of the definitions of hormone independence, quality-of-life outcomes, and surrogate markers of response have led to improved standardization across clinical trials that allow for head to head comparisons of active agents.12,13 The earlier detection of biochemical recurrence and asymptomatic metastatic disease with the use of serum PSA measurements and improved imaging techniques may also translate into the earlier initiation of therapy before disease burden and pain become overwhelming factors. While hormone-refractory metastatic prostate cancer remains an incurable disease, chemotherapy has come to play a role in prolonging patient survival with meaningful quality-of-life endpoints and has generated optimism about progress among both clinicians and patients.

Authors
Armstrong, AJ; Carducci, MA
MLA Citation
Armstrong, AJ, and Carducci, MA. "Chemotherapy for advanced prostate cancer." Prostate Cancer: Principles and Practice. January 1, 2005. 989-1003.
Source
scopus
Publish Date
2005
Start Page
989
End Page
1003

Workplace discrimination and cumulative trauma disorders: the national EEOC ADA research project.

Employment discrimination of persons with cumulative trauma disorders (CTDs) was explored using the Integrated Mission System dataset of the US Equal Employment Opportunity Commission. Demographic characteristics and merit resolutions of the Charging Parties (persons with CTD) were compared to individuals experiencing other physical, sensory and neurological impairments. Factors compared also included industry designation, geographic region, and size of Respondents against which allegations were filed. Persons with CTD had proportionately greater allegations among large Respondents (greater than 500 workers) engaged in manufacturing, utilities, transportation, finance insurance and real estate. The types of discrimination Issues that were proportionately greater in the CTD group included layoff, failure to reinstate, and failure to provide reasonable accommodation. The CTD group was significantly less likely than the comparison group to be involved in discrimination Issues such as assignment to less desirable duty, shift or work location; demotion; termination, or failure to hire or provide training. Persons with CTD had higher proportions of merit Resolutions where allegations were voluntarily withdrawn by the Charging Party with benefits.

Authors
Armstrong, AJ; McMahon, BT; West, SL; Lewis, A
MLA Citation
Armstrong, AJ, McMahon, BT, West, SL, and Lewis, A. "Workplace discrimination and cumulative trauma disorders: the national EEOC ADA research project." Work 25.1 (2005): 49-56.
PMID
16006675
Source
pubmed
Published In
Work (Reading, Mass.)
Volume
25
Issue
1
Publish Date
2005
Start Page
49
End Page
56

EpCAM is an important suppressor of anti-tumor immunity [2]

Authors
Eck, SL; Armstrong, A
MLA Citation
Eck, SL, and Armstrong, A. "EpCAM is an important suppressor of anti-tumor immunity [2]." Cancer Biology and Therapy 4.4 (2005): e129-.
Source
scival
Published In
Cancer Biology and Therapy
Volume
4
Issue
4
Publish Date
2005
Start Page
e129

EpCAM: A new therapeutic target for an old cancer antigen

The use of monoclonal antibodies as adjuvants to cancer chemotherapy has drawn considerable interest in recent years, due to the success of several novel agents against a broad range of targets. One such target is EpCAM (aka GA733-2, KSA, 17-1A antigen), a human cell surface glycoprotein expressed on some normal and most neoplastic epithelial cells. It is now widely recognized as having an important role in tumor biology, especially in colorectal cancer, and since its original discovery in the early 1980's, the known mechanism by which it functions has steadily evolved. Initial studies of monoclonal antibodies directed against EpCAM demonstrated the presence of anti-idiotype networks involving both B and T cells, antibody-dependent cell cytotoxicity, and complement mediated cell death as mechanisms of tumor growth inhibition. Recently, a novel receptor for EpCAM has been described that is a member of the inhibitory group of immunoglobulin-like receptors and is present on lymphocytes, monocytes, dendritic cells, and NK cells. Neoplastic cells that interact with this receptor, named LAIR-1, may enact an immunologic escape, and thus confer a selective advantage for their growth and spread. This novel mechanism of action may add to our current understanding of how monoclonal antibodies targeted against EpCAM inhibit tumor growth. Passive vaccination with this antibody may induce a tertiary anti-idiotypic network which correlates with clinical outcome, but the mechanism behind this outcome in select patients with minimal residual disease may additionally involve a novel blockade of tumor specific immunosuppression. This review will focus on the initial discoveries of EpCAM's cellular adhesion properties, its role in normal and neoplastic cell function, its distribution and presumed mechanism of action, and clinical studies of EpCAM as a therapeutic target. Clinical trials of edrecolomab, one such monoclonal antibody, in patients with colon cancer will be reviewed and updated. While phase III trials of edrecolomab have not demonstrated improved efficacy as adjuvant therapy for stage III colon cancer, newer agents with improved affinity, less chimerism, and improved delivery may still demonstrate benefit. ©2003 Landes Bioscience.

Authors
Armstrong, A; Eck, SL
MLA Citation
Armstrong, A, and Eck, SL. "EpCAM: A new therapeutic target for an old cancer antigen." Cancer Biology and Therapy 2.4 (2003): 320-325.
PMID
14508099
Source
scival
Published In
Cancer Biology & Therapy
Volume
2
Issue
4
Publish Date
2003
Start Page
320
End Page
325
DOI
10.4161/cbt.2.4.451

Inertial properties and loading rates affect buckling modes and injury mechanisms in the cervical spine.

Cervical spine injuries continue to be a costly societal problem. Future advancements in injury prevention depend on improved physical and computational models which, in turn, are predicated on a better understanding of the responses of the neck during dynamic loading. Previous studies have shown that the tolerance of the neck is dependent on its initial position and its buckling behavior. This study uses a computational model to examine the mechanical factors influencing buckling behavior during impact to the neck. It was hypothesized that the inertial properties of the cervical spine influence the dynamics during compressive axial loading. The hypothesis was tested by performing parametric analyses of vertebral mass, mass moments of inertia, motion segment stiffness, and loading rate. Increases in vertebral mass resulted in increasingly complex kinematics and larger peak loads and impulses. Similar results were observed for increases in stiffness. Faster loading rates were associated with higher peak loads and higher-order buckling modes. The results demonstrate that mass has a great deal of influence on the buckling behavior of the neck, particularly with respect to the expression of higher-order modes. Injury types and mechanisms may be substantially altered by loading rate because inertial effects may influence whether the cervical spine fails in a compressive mode, or a bending mode.

Authors
Nightingale, RW; Camacho, DL; Armstrong, AJ; Robinette, JJ; Myers, BS
MLA Citation
Nightingale, RW, Camacho, DL, Armstrong, AJ, Robinette, JJ, and Myers, BS. "Inertial properties and loading rates affect buckling modes and injury mechanisms in the cervical spine." J Biomech 33.2 (February 2000): 191-197.
PMID
10653032
Source
pubmed
Published In
Journal of Biomechanics
Volume
33
Issue
2
Publish Date
2000
Start Page
191
End Page
197

Cervical spine buckling: The effects of vertebral mass and loading rate

Authors
Nightingale, RW; Armstrong, AJ; Camacho, DL; Myers, BS
MLA Citation
Nightingale, RW, Armstrong, AJ, Camacho, DL, and Myers, BS. "Cervical spine buckling: The effects of vertebral mass and loading rate." American Society of Mechanical Engineers, Bioengineering Division (Publication) BED 36 (1997): 231-232.
Source
scival
Published In
American Society of Mechanical Engineers, Bioengineering Division (Publication) Bed
Volume
36
Publish Date
1997
Start Page
231
End Page
232

Mutagenic analysis of functional domains of the mos proto-oncogene and identification of the sites important for MAPK activation and DNA binding.

We constructed in-frame deletion/replacement mutations in the Xenopus mos proto-oncogene that lie within conserved Mos-specific codons, but outside of the regions that are conserved among the src kinase family of genes. All gene products were assayed in vitro for kinase activity and in vivo for their ability to induce oocyte maturation, embryonic cleavage arrest and cellular transformation. Most mutations in Mos eliminated both kinase and biological activity. However, a mutation in Mos that removed two basic amino acid residues (R94 and K97) downstream from the lysine at the ATP binding site (K90) markedly enhanced autophosphorylation activity. Moreover, this mutant displayed markedly reduced biological activity, lacked transforming activity, and failed to activate mitogen activated protein kinase (MAPK). A second mutant Mos product, lacking amino acids R45-A54, displayed a five-fold increase in cellular transforming activity. This Mos mutant specifically localized to the cytoplasm; in contrast to wild-type (wt) Mos that localized to both the nucleus and the cytoplasm. These data indicate that Mos transforming activity is mediated via signalling exerted in the cytoplasm, presumably through MAPK, and that nuclear localization of the oncogene product interferes with transforming activity. We also show that amino acids R45-A54 are important for Mos DNA binding activity.

Authors
Fukasawa, K; Zhou, R; Matten, WT; Armstrong, AJ; Daar, I; Oskarsson, M; Sathyanarayana, BK; Maclvor, L; Wood, TG; Vande Woude, GF
MLA Citation
Fukasawa, K, Zhou, R, Matten, WT, Armstrong, AJ, Daar, I, Oskarsson, M, Sathyanarayana, BK, Maclvor, L, Wood, TG, and Vande Woude, GF. "Mutagenic analysis of functional domains of the mos proto-oncogene and identification of the sites important for MAPK activation and DNA binding." Oncogene 11.8 (October 19, 1995): 1447-1457.
PMID
7478569
Source
pubmed
Published In
Oncogene
Volume
11
Issue
8
Publish Date
1995
Start Page
1447
End Page
1457

Vortex Mutual Friction in Rotating Superfluid 3He-B.

Authors
Bevan, TD; Manninen, AJ; Cook, JB; Armstrong, AJ; Hook, JR; Hall, HE
MLA Citation
Bevan, TD, Manninen, AJ, Cook, JB, Armstrong, AJ, Hook, JR, and Hall, HE. "Vortex Mutual Friction in Rotating Superfluid 3He-B." Phys Rev Lett 74.5 (January 30, 1995): 750-753.
PMID
10058838
Source
pubmed
Published In
Phys Rev Lett
Volume
74
Issue
5
Publish Date
1995
Start Page
750
End Page
753
DOI
10.1103/PhysRevLett.74.750

Identification of the order parameter of 3He-A using low-field NMR measurements.

Authors
Mullins, TR; Dmitriev, VV; Armstrong, AJ; Manninen, AJ; Hook, JR; Hall, HE
MLA Citation
Mullins, TR, Dmitriev, VV, Armstrong, AJ, Manninen, AJ, Hook, JR, and Hall, HE. "Identification of the order parameter of 3He-A using low-field NMR measurements." Phys Rev Lett 72.26 (June 27, 1994): 4117-4120.
PMID
10056386
Source
pubmed
Published In
Phys Rev Lett
Volume
72
Issue
26
Publish Date
1994
Start Page
4117
End Page
4120
DOI
10.1103/PhysRevLett.72.4117

Free-expansion melting of a colloidal monolayer.

Authors
Tang, Y; Armstrong, AJ; Mockler, RC; O'Sullivan, WJ
MLA Citation
Tang, Y, Armstrong, AJ, Mockler, RC, and O'Sullivan, WJ. "Free-expansion melting of a colloidal monolayer." Phys Rev Lett 62.20 (May 15, 1989): 2401-2404.
PMID
10039976
Source
pubmed
Published In
Phys Rev Lett
Volume
62
Issue
20
Publish Date
1989
Start Page
2401
End Page
2404
DOI
10.1103/PhysRevLett.62.2401

Changes in pancreatic tryptophan in the rat in response to fasting. The effect of B-cytotoxic agents and variation through the oestrous cycle.

The concentration of tryptophan not incorporated into protein or polypeptides in the pancreas of male rats rose two- to three-fold in response to a 24 hrs period of food deprivation. On refeeding or intra-peritoneal administration of glucose the level of tryptophan in the pancreas fell, while that in the serum rose. The pancrease B-cytotoxic agents alloxan and streptozotocin both abolished this response to fasting, while neutral red (an A-cytotoxic agent) had no effect. It therefore appears that the tryptophan which accumulates in the pancreas during fasting is located mainly in the B-cells of the Islets of Langerhans. In female rats, the concentration of tryptophan in the pancreas was greater at dioestrus than at any other stage of the oestrous cycle. The increase in pancreatic tryptophan was maximal at metoestrus and minimal at oestrus.

Authors
Bender, DA; Armstrong, AJ; Monkhouse, CR; Richardson, JP
MLA Citation
Bender, DA, Armstrong, AJ, Monkhouse, CR, and Richardson, JP. "Changes in pancreatic tryptophan in the rat in response to fasting. The effect of B-cytotoxic agents and variation through the oestrous cycle." Pflugers Arch 356.3 (1975): 245-251.
PMID
125406
Source
pubmed
Published In
Pflügers Archiv European Journal of Physiology
Volume
356
Issue
3
Publish Date
1975
Start Page
245
End Page
251

Changes in skeletal muscle cross sectional area (CSA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZ).

Background: Phase III studies that led to ENZ approval in the treatment of mCRPC included side effects like fatigue, musculoskeletal pain, and falls, which could result from skeletal muscle loss. Such muscle loss (sarcopenia), in a variety of cancer populations, is correlated with mortality. While conventional androgen deprivation therapy in prostate cancer is known to cause sarcopenia, there is a paucity of data with next generation androgen receptor directed therapies like ENZ. Methods: Through query of pharmacy records, we conducted a retrospective analysis of patientstreated with ENZ prior to the use of docetaxel for mCRPC from April 28, 2011 - June 15, 2015 at Duke University. We included patients with a computed tomography (CT) scan available for analysis of skeletal muscle cross sectional area (CSA) both at baseline (+/- 6 wks) and after 6 months (+/- 6 wks) of treatment with ENZ. Muscle CSA was measured using the Slice-O-Matic (TomoVision, Montreal CA) at the level of the third lumbar vertebrae (L3) by a trained reviewer, and each measurement was verified and edited at the discretion of a second trained reviewer. The primary objective was to determine the change in muscle CSA at L3 from baseline to 6 mos of ENZ treatment (tx). Results: At the time of ENZ initiation (baseline),characteristics of 39 patients identified included a median age 74, ECOG performance status 0, BMI 30.4 kg/m2, time on ADT of 43.5 mos prior, Gleason score 8, and PSA 13.7 ng/mL. Across all time points, concordance between reviewers was high, r > 0.99. Mean CSA differed significantly from baseline (153.9 cm2, standard deviation = 30.17) to 6 months ENZ tx (145.4 cm2, standard deviation = 29.9; paired t-test p < 0.0001). In a sub-group (n = 13) with 3 measurements available (CT scan 6 mos pre-ENZ tx, baseline, and 6 mos post-ENZ tx), there was a significant change in CSA from baseline to 6 mos post-ENZ tx (paired t-test p = 0.0356), but no change from pre-ENZ tx to baseline (p = 0.1065). Conclusions: Patients treated with ENZ had significant muscle loss after six months of treatment. Prospective studies of exercise interventions to mitigate ENZ skeletal muscle toxicity are underway (NCT02256111).

Authors
Ramalingam, S; Sermer, D; Gupta, R; Healy, P; Wu, Y; George, D; Armstrong, A; Harrison, MR
MLA Citation
Ramalingam, S, Sermer, D, Gupta, R, Healy, P, Wu, Y, George, D, Armstrong, A, and Harrison, MR. "Changes in skeletal muscle cross sectional area (CSA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZ)." Journal of Clinical Oncology 34.
Source
manual
Published In
Journal of Clinical Oncology
Volume
34
DOI
10.1200/JCO.2016.34.15\_suppl.e16601
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