Oral SERDs and Overcoming ESR1-Mediated Endocrine Resistance

In this segment, Drs. Mouabbi and Bardia focus on the emergence of oral SERDs as a meaningful advance for patients with ESR1-mutant, ER-positive metastatic breast cancer. Dr. Bardia reviews the rationale and design of the EMERALD trial, which evaluated elacestrant in patients previously treated with CDK4/6 inhibitors in the second-line and later settings. At the time of trial design, endocrine monotherapy remained a common option after progression, creating an opportunity to compare a novel oral SERD with standard-of-care endocrine therapies, primarily fulvestrant, with AIs also permitted.

A key design consideration was whether to study all patients or focus on those with ESR1 mutations. Because ESR1 mutations signal ongoing estrogen receptor dependence despite resistance to AIs, they were included as a co–primary endpoint alongside the intention-to-treat population. EMERALD ultimately demonstrated statistically significant benefit in both groups, with a larger magnitude of benefit observed in patients with ESR1-mutant disease. Based on these results, elacestrant received FDA approval as a standard endocrine therapy option for patients with detectable ESR1 mutations.

Dr. Mouabbi highlights the rigorous nature of the EMERALD trial, noting its heavily pretreated population and inclusion of patients often excluded from clinical trials, such as those with primary endocrine resistance or prior chemotherapy. He cautions against cross-trial comparisons with other oral SERD studies, such as EMBER-3, which evaluated imlunestrant in a different, less heavily treated population and showed benefit primarily in ESR1-mutant tumors.

The conversation then turns to real-world evidence. Dr. Bardia notes that observational data, including analyses led by Dr. Mouabbi’s group, demonstrate progression-free survival outcomes with elacestrant that closely mirror those seen in EMERALD, particularly when used earlier after CDK4/6 inhibitor therapy. This alignment between clinical trial and real-world data reinforces the clinical utility of oral SERDs and supports their integration into routine practice, especially in the second-line setting where the greatest benefit is observed.