Dr Rugo on Elacestrant-Based Combos in ER+/HER2– Locally Advanced or Metastatic Breast Cancer

“The efficacy of combining everolimus with elacestrant is maintained across the different subsets we were able to analyze.”

Hope S. Rugo, MD, professor in the Department of Medical Oncology and Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women’s Cancers Program at City of Hope, discussed results from the phase 2 ELEVATE trial (NCT05563220), an open-label umbrella study evaluating elacestrant (Orserdu) in combination with everolimus (Afinitor) or abemaciclib (Verzenio) in patients with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer.

ELEVATE was designed to explore whether elacestrant—an oral selective estrogen receptor degrader (SERD)—could serve as an effective backbone endocrine partner when combined with agents targeting key resistance pathways. Given the emergence of ESR1 mutations and hormone-resistant disease following prior endocrine therapy and CDK4/6 inhibition, investigators assessed elacestrant in combination with with either everolimus, an mTOR inhibitor, or abemaciclib, a CDK4/6 inhibitor, to characterize safety, tolerability, and signals of antitumor activity. Findings were presented at the 2025 San Antonio Breast Cancer Symposium.

Rugo explained that patients were enrolled into cohorts based on prior therapy and clinical characteristics, with all participants having received at least 1 line of endocrine therapy in the metastatic setting. Patients did need to be naive to chemotherapy in the metastatic setting.

Both combinations demonstrated manageable safety profiles consistent with known toxicities of each partner drug. The most frequent adverse effects included gastrointestinal toxicities with abemaciclib and stomatitis, fatigue, and metabolic abnormalities with everolimus; however, elacestrant did not introduce unexpected safety concerns in combination.

Regarding efficacy, early activity signals suggested clinical benefit across cohorts. In the everolimus group (n = 50), the combination produced a median progression-free survival (PFS) of 8.3 months (95% CI, 4.0-10.2) and an overall response rate (ORR) of 19.5%. In patients treated with elacestrant plus abemaciclib (n = 60), the median PFS was 14.3 months (95% CI, 7.3-16.6), and the ORR was 24.6%. Rugo highlighted that responses were observed irrespective of ESR1 mutation status, supporting the potential versatility of oral SERD-based combination therapy across molecular subsets. Although follow-up remains ongoing, Rugo noted that the emerging data reinforce the rationale for pairing endocrine agents with targeted therapies aimed at bypass or resistance pathways to extend disease control.

Rugo emphasized that the phase 2 results provide a foundation for future development of elacestrant-based combinations in patients with ER-positive/HER2-negative metastatic breast cancer. As resistance to endocrine therapy continues to challenge long-term disease management, optimizing rational SERD/targeted therapy combinations may help address unmet needs in this population.