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.
The American Cancer Society released its 2025 statistics publications, offering insights into cancer incidence, mortality, treatment and survival.Rising Cancer Incidence Rates in Younger WomenThis year’s report reveals that for women younger than 50, the risk of developing cancer is 82 percent higher than men, up from 51 percent in 2022. This marks the first time cancer incidence rates in women under 50 have surpassed men.A main contributor to this higher incidence rate is breast cancer, which predominantly affects women. Higher obesity rates, increased alcohol use, and later-in-life pregnancies have long been identified as risk factors for breast cancer; however, there are still lots of unknowns.“I often see women coming into my clinic with breast cancer who ‘did all the right things,’” said Jennifer Plichta, MD, MS, breast surgical oncologist and provider for the Duke Breast Risk Assessment Clinic. “We know some of the risk factors, but I think that we still struggle with how those risk factors come together.”While there are many examples of breast cancer research and prevention efforts for women over 50, younger women are often less involved in those efforts. Plichta said some of the reason for that may have to do with the severity of side effects of breast cancer prevention options – most commonly, surgeries that cause permanent changes to the body and medications that often produce menopausal symptoms and may make it more difficult to conceive.In view of rising incidence rates in younger women, Plichta believes it’s important for providers to clearly communicate with patients to help them really understand their risk factors and make the best choice for themselves. Plichta currently leads the Breast Risk Assessment Clinic, which focuses on understanding breast cancer risk and personalizing management strategies. Additionally, Rani Bansal, MD, a breast medical oncologist, is working on opening a clinic specifically focused on young breast cancer patients.“It’s a real worry that more younger women are getting breast cancer,” she said. “We need to start having conversations with them earlier and more often so they can know what to do.”Improving Survival Rates, Except in Uterine CancersThe incidence and mortality of many cancer types is declining in the U.S., but uterine cancer cases have been increasing by about one percent per year, and even more among non-white women. Andrew Berchuck, MD, director of the DCI gynecologic cancer group, notes this increase is mostly due to high obesity rates.“Obesity causes excessive production of estrogenic hormones that can stimulate growth and cancer development in the uterine lining,” Berchuck said. “Reducing obesity rates is important from a broad health perspective and would also reverse the rise in uterine cancer incidence.”Since 1975, the five-year survival rate for uterine cancer has decreased from 87 percent to 81 percent. It is now the fifth leading cause of cancer deaths in women. Additionally, uterine cancer has one of the largest racial disparities in survival – 84 percent in white patients, compared to 63 percent in Black patients.To address these trends, DCI researchers have developed a national uterine cancer consortium looking into molecular features of these cancers to help develop new targeted therapies, led by Angeles Secord, MD, associate director of the DCI gynecologic cancer group. The efforts of the consortium are highlighted at the annual She Dunks on Endometrial Cancer, taking place on Feb. 23 this year.“Duke is helping lead the charge in improving treatment for uterine cancer,” Berchuck said. “We are hopeful that our efforts can lead to better outcomes for our patients in the future.”
The American Cancer Society released its 2025 statistics publications, offering insights into cancer incidence, mortality, treatment and survival.Rising Cancer Incidence Rates in Younger WomenThis year’s report reveals that for women younger than 50, the risk of developing cancer is 82 percent higher than men, up from 51 percent in 2022. This marks the first time cancer incidence rates in women under 50 have surpassed men.A main contributor to this higher incidence rate is breast cancer, which predominantly affects women. Higher obesity rates, increased alcohol use, and later-in-life pregnancies have long been identified as risk factors for breast cancer; however, there are still lots of unknowns.“I often see women coming into my clinic with breast cancer who ‘did all the right things,’” said Jennifer Plichta, MD, MS, breast surgical oncologist and provider for the Duke Breast Risk Assessment Clinic. “We know some of the risk factors, but I think that we still struggle with how those risk factors come together.”While there are many examples of breast cancer research and prevention efforts for women over 50, younger women are often less involved in those efforts. Plichta said some of the reason for that may have to do with the severity of side effects of breast cancer prevention options – most commonly, surgeries that cause permanent changes to the body and medications that often produce menopausal symptoms and may make it more difficult to conceive.In view of rising incidence rates in younger women, Plichta believes it’s important for providers to clearly communicate with patients to help them really understand their risk factors and make the best choice for themselves. Plichta currently leads the Breast Risk Assessment Clinic, which focuses on understanding breast cancer risk and personalizing management strategies. Additionally, Rani Bansal, MD, a breast medical oncologist, is working on opening a clinic specifically focused on young breast cancer patients.“It’s a real worry that more younger women are getting breast cancer,” she said. “We need to start having conversations with them earlier and more often so they can know what to do.”Improving Survival Rates, Except in Uterine CancersThe incidence and mortality of many cancer types is declining in the U.S., but uterine cancer cases have been increasing by about one percent per year, and even more among non-white women. Andrew Berchuck, MD, director of the DCI gynecologic cancer group, notes this increase is mostly due to high obesity rates.“Obesity causes excessive production of estrogenic hormones that can stimulate growth and cancer development in the uterine lining,” Berchuck said. “Reducing obesity rates is important from a broad health perspective and would also reverse the rise in uterine cancer incidence.”Since 1975, the five-year survival rate for uterine cancer has decreased from 87 percent to 81 percent. It is now the fifth leading cause of cancer deaths in women. Additionally, uterine cancer has one of the largest racial disparities in survival – 84 percent in white patients, compared to 63 percent in Black patients.To address these trends, DCI researchers have developed a national uterine cancer consortium looking into molecular features of these cancers to help develop new targeted therapies, led by Angeles Secord, MD, associate director of the DCI gynecologic cancer group. The efforts of the consortium are highlighted at the annual She Dunks on Endometrial Cancer, taking place on Feb. 23 this year.“Duke is helping lead the charge in improving treatment for uterine cancer,” Berchuck said. “We are hopeful that our efforts can lead to better outcomes for our patients in the future.”
