From the Duke Cancer Institute archives. Content may be out of date.
Suzanne Wardell
Research that originated in a Duke Cancer Institute (DCI) laboratory contributed to Food and Drug Administration (FDA) approval of the first new endocrine therapy for breast cancer since 2002, and the only drug designed to target mutations in estrogen receptor 1 (ESR1).
Donald McDonnell, PhD, associate director For translational research at DCI and the Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, directed the research team that led to the development of elacestrant (Orserdu, Stemline Therapeutics, Inc).
The new therapy, a selective estrogen receptor down-regulator (SERD), is indicated for the treatment of postmenopausal women or adult men with estrogen-receptor-positive/HER2-negative ESR1-mutated advanced or metastatic breast cancer who have been treated unsuccessfully with at least one previous endocrine therapy.
The FDA approved the therapy in January 2023.
Meeting a Need
Erik Nelson
The drug is the only SERD that can be taken orally, which makes it more convenient for patients. McDonnell said it fills a significant unmet need because up to 40% of patients diagnosed with ER-positive/HER2-negative breast cancer will acquire ESR1 mutations as the cancer advances. In most cases, these mutations will trigger resistance to standard endocrine therapies.
During the past decade, the McDonnell Lab has been focused on identifying and developing new endocrine therapies to treat advanced ER-positive breast cancer. This initiative has included revisiting older hormone therapies originally developed to treat osteoporosis or menopause symptoms.
Elacestrant, for example, was developed initially to treat hot flashes in post-menopausal women but was never approved for that use. Clinical trials demonstrated that RAD1901, as the therapy was known, stopped hot flashes at low doses but increased them at higher doses. McDonnell and researchers in his lab were intrigued by the pharmacology. “It turns out that the reason for RAD1901’s failure as a treatment for hot flashes was a useful property for a breast cancer drug,” McDonnell said.
Investigators who were trainees in the McDonnell Lab at the time, Suzanne E. Wardell, PhD, and Erik Nelson, PhD, determined that RAD1901 was effective at blocking the estrogen driving cancer cell growth by binding to its receptor, like a selective estrogen receptor modulator(SERM), and degrading the estrogen receptor, like a SERD.
Wardell and Nelson went on to demonstrate that RAD1901 inhibited tumor growth in mouse models. This was the springboard for continued investigations worldwide; culminating in the successful multicenter phase 3 clinical trial (EMERALD 2018–2022) that led to FDA approval. Wardell is now an assistant professor of pharmacology and cancer biology at Duke, in McDonnell’s lab. Nelson is now a professor of molecular and integrative physiology at the University of Illinois Urbana-Champaign.
“We’re already prescribing elacestrant for our patients,” said Heather Moore, CPP, PharmD, a clinical pharmacist with Duke Health, noting that the drug is currently being distributed nationally by two specialty pharmacies.
For many people with lung cancer, the disease doesn’t stay confined to the lungs. Up to half of patients with non-small cell lung cancer, and as many as 80 percent of patients with small cell lung cancer, develop brain metastases throughout the course of their illness. These diagnoses can significantly affect quality of life, treatment options, and long-term outcomes.At Duke Cancer Institute (DCI), Laura Alder, MD, deputy director of medical oncology for the Duke Center for Brain and Spine Metastasis, is working to change how patients with brain metastases are represented in clinical research and, ultimately, how they are treated.Alder’s clinical and research career centers on two closely related priorities: lung cancer and brain metastases. After completing her fellowship at Duke, she joined the faculty and became deeply involved in multidisciplinary efforts to improve care for patients whose cancer has spread to the brain or spine.“Brain metastases have a huge impact on a patient’s trajectory,” Alder said. “They affect quality of life, treatment decisions, and outcomes in very meaningful ways.”Clinical trials often represent the most promising treatment option for patients with advanced cancer, offering access to therapies that are not yet widely available. However, Alder notes that trial eligibility criteria have traditionally been narrow.“There’s been a longstanding concern that patients with brain metastases wouldn’t do well on clinical trials or could confound the results,” Alder said. “As a result, many trials exclude these patients entirely.”To address this gap, Alder collaborated with a multidisciplinary group of researchers on a publication focused on improving clinical trial inclusion for patients with lung cancer and brain metastases. The work, published recently in Lung Cancer, builds on decades of research led by Paul Sperduto, MD, PhD, adjunct professor in the Duke Department of Radiation Oncology, who developed the Graded Prognostic Assessment (GPA).The GPA is a validated tool used to estimate survival in patients with brain metastases by accounting for factors such as age, performance status, disease burden, and tumor biology. For non-small cell lung cancer, the tool incorporates modern biomarkers, including genetic driver mutations, which can influence response to targeted immunotherapies.Paired with the eligibility quotient (EQ), which helps estimate conditional survival, these tools paint a more accurate and individualized picture of prognosis, one that challenges outdated assumptions.“What we see is that many of these patients actually have very good overall survival,” Alder said. “Our therapies are better, more precise, and more effective than ever before.”Alder said advances in imaging, MRI surveillance, and radiation techniques, such as stereotactic radiosurgery (SRS), also make it possible to closely monitor and manage brain metastases during treatment. These innovations further support the safe inclusion of these patients in trials.At Duke, efforts to improve clinical trial inclusivity extend beyond a single publication. Through the Duke Center for Brain and Spine Metastasis, clinicians and researchers regularly collaborate with pharmaceutical partners, advocate at national conferences, and engage in ongoing dialogue with industry leaders.“This has been a mission for many of us for years,” Alder said. “At every meeting, every podium, we’re making the case that these patients need to be included because that’s where the unmet need is.”Encouragingly, progress is being made. National organizations such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), along with the U.S. Food and Drug Administration (FDA), have increasingly emphasized the importance of broader eligibility criteria in cancer trials.Alder hopes the framework outlined in the publication will be used prospectively in future trials, helping demonstrate that inclusion of patients with brain metastases is both safe and beneficial.“Our patients are living longer than ever before,” she says. “They deserve clinical trials that reflect the reality of their disease and give us the data we need to keep making progress.”
For many people with lung cancer, the disease doesn’t stay confined to the lungs. Up to half of patients with non-small cell lung cancer, and as many as 80 percent of patients with small cell lung cancer, develop brain metastases throughout the course of their illness. These diagnoses can significantly affect quality of life, treatment options, and long-term outcomes.At Duke Cancer Institute (DCI), Laura Alder, MD, deputy director of medical oncology for the Duke Center for Brain and Spine Metastasis, is working to change how patients with brain metastases are represented in clinical research and, ultimately, how they are treated.Alder’s clinical and research career centers on two closely related priorities: lung cancer and brain metastases. After completing her fellowship at Duke, she joined the faculty and became deeply involved in multidisciplinary efforts to improve care for patients whose cancer has spread to the brain or spine.“Brain metastases have a huge impact on a patient’s trajectory,” Alder said. “They affect quality of life, treatment decisions, and outcomes in very meaningful ways.”Clinical trials often represent the most promising treatment option for patients with advanced cancer, offering access to therapies that are not yet widely available. However, Alder notes that trial eligibility criteria have traditionally been narrow.“There’s been a longstanding concern that patients with brain metastases wouldn’t do well on clinical trials or could confound the results,” Alder said. “As a result, many trials exclude these patients entirely.”To address this gap, Alder collaborated with a multidisciplinary group of researchers on a publication focused on improving clinical trial inclusion for patients with lung cancer and brain metastases. The work, published recently in Lung Cancer, builds on decades of research led by Paul Sperduto, MD, PhD, adjunct professor in the Duke Department of Radiation Oncology, who developed the Graded Prognostic Assessment (GPA).The GPA is a validated tool used to estimate survival in patients with brain metastases by accounting for factors such as age, performance status, disease burden, and tumor biology. For non-small cell lung cancer, the tool incorporates modern biomarkers, including genetic driver mutations, which can influence response to targeted immunotherapies.Paired with the eligibility quotient (EQ), which helps estimate conditional survival, these tools paint a more accurate and individualized picture of prognosis, one that challenges outdated assumptions.“What we see is that many of these patients actually have very good overall survival,” Alder said. “Our therapies are better, more precise, and more effective than ever before.”Alder said advances in imaging, MRI surveillance, and radiation techniques, such as stereotactic radiosurgery (SRS), also make it possible to closely monitor and manage brain metastases during treatment. These innovations further support the safe inclusion of these patients in trials.At Duke, efforts to improve clinical trial inclusivity extend beyond a single publication. Through the Duke Center for Brain and Spine Metastasis, clinicians and researchers regularly collaborate with pharmaceutical partners, advocate at national conferences, and engage in ongoing dialogue with industry leaders.“This has been a mission for many of us for years,” Alder said. “At every meeting, every podium, we’re making the case that these patients need to be included because that’s where the unmet need is.”Encouragingly, progress is being made. National organizations such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), along with the U.S. Food and Drug Administration (FDA), have increasingly emphasized the importance of broader eligibility criteria in cancer trials.Alder hopes the framework outlined in the publication will be used prospectively in future trials, helping demonstrate that inclusion of patients with brain metastases is both safe and beneficial.“Our patients are living longer than ever before,” she says. “They deserve clinical trials that reflect the reality of their disease and give us the data we need to keep making progress.”
