Group photo of Donald McDonnell lab members standing on a balcony
Members of the Donald McDonnell lab in 2022

A New Option for Advanced Breast Cancer

Headshot of Suzanne Wardell, PhD
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.

Headshot of Eric Nelson, PhD
Erik Nelson

Meeting a Need

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.

This story was originally published in Clinical Practice Today.

This page was reviewed on 10/16/2023