Looking Ahead: Oral SERD Combination Strategies and the Evolving Role of Biomarker Testing in ESR1-Mutant Breast Cancer

In this forward-looking segment, Drs. Mouabbi and Bardia explore emerging combination strategies involving oral SERDs and targeted agents, and how these data may influence future treatment sequencing. Dr. Mouabbi highlights recent studies evaluating combinations such as imlunestrant with abemaciclib in EMBER-3, elacestrant with everolimus or abemaciclib in the ELEVATE trial, and giredestrant with everolimus in the AVERA study. Collectively, these trials signal a shift toward combination regimens aimed at improving efficacy beyond what can be achieved with endocrine monotherapy.

Dr. Bardia summarizes the key efficacy signals observed to date. In EMBER-3, the combination of imlunestrant plus abemaciclib outperformed imlunestrant alone. Single-arm data from ELEVATE demonstrated encouraging activity for both elacestrant plus everolimus and elacestrant plus abemaciclib, with median progression-free survival ranging from approximately 9–10 months with everolimus to up to 14 months with abemaciclib. Although cross-trial comparisons are cautioned against, these results suggest meaningful clinical activity without significant drug–drug interactions.

The discussion also emphasizes the trade-off between improved efficacy and increased toxicity. Combination regimens introduce overlapping adverse events, including high rates of diarrhea with imlunestrant plus abemaciclib, mucositis with everolimus-based combinations, and myelosuppression with CDK4/6 inhibitors. As a result, Dr. Bardia stresses the importance of “right-sizing” therapy for individual patients, favoring monotherapy when appropriate and reserving combinations for patients who require deeper or faster disease control.

The segment concludes with a nuanced discussion on biomarker testing in the era of combination therapy. Both speakers agree that testing should only be performed if it will directly influence treatment decisions. Although combination approaches may reduce reliance on ESR1 status in some scenarios, mutation testing remains essential when considering monotherapy or tailoring treatment strategies, reinforcing the principle of purposeful, action-driven precision oncology.