Background
Disease progression in patients with estrogen receptor–positive (ER+)/HER2-negative (HER2–) metastatic breast cancer on first-line endocrine therapy (ET) plus CDK4/6 inhibitor (CDK4/6i) is associated with resistance mechanisms that impact the efficacy of subsequent therapy, which may include ET with or without targeted agents (CDK4/6i or PI3K/AKT/mTOR pathway inhibitors). Clinical trials have shown median progression-free survival (PFS) of 3.6 to 6.8 months with ET plus everolimus and 5.3 to 9.4 months with a CDK4/6i switch. Elacestrant significantly improved PFS vs standard of care (SOC) ET (ESR1-mutated tumors HR, 0.55; 95% CI 0.39-0.77; all patients HR, 0.70; 95% CI 0.55-0.88) with manageable safety in the EMERALD trial. Based on encouraging phase 1b clinical activity and tolerability, we evaluated phase 2 combinations of elacestrant plus everolimus or abemaciclib in all patients and subgroups.
Methods
ELEVATE is evaluating elacestrant combined with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib to address different resistance mechanisms. Patients with ER+/HER2– metastatic breast cancer and 1 to 2 lines of prior ET are eligible regardless of ESR1 mutation status. Prior CDK4/6i is required for arm B (elacestrant plus everolimus) and arm C (everolimus plus abemaciclib). Patients with no prior CDK4/6i were enrolled in arm D (elacestrant plus abemaciclib). Phase 2 objective is to evaluate PFS with each combination. ESR1 and PIK3CA mutation status were evaluated in patients for both combinations elacestrant plus everolimus (n = 48) and elacestrant plus abemaciclib (n = 50). Additional translational analyses are being performed.
Results
As of September 2025, 50 patients enrolled in arm B (elacestrant plus everolimus), and 60 enrolled in arms C and D (elacestrant plus abemaciclib combinations, n = 30 each). Key baseline characteristics include pts with visceral metastases (72% arm B, 92% arms C/D), primary ET resistance (20% arm B, 15% arms C/D), ESR1 mutation (42% arm B, 33% arms C/D), and PIK3CA mutation (50% arm B, 27% arms C/D). PFS was consistent across subgroups, including those with visceral metastases, prior fulvestrant or primary ET resistance (Table). Safety with the elacestrant combinations were consistent with the known safety profiles of everolimus plus abemaciclib plus SOC ET. Phase 2 elacestrant plus everolimus overall response rate (ORR) was 19.5%, stable disease (SD) 63.4%, disease control rate (DCR) 82.9%, and median duration of response (DOR) 8.54 months. Phase 2 elacestrant plus abemaciclib ORR was 24.6%, SD 66.7%, DCR 91.2%, and median DOR 14.75 months. Median follow-up period for elacestrant plus abemaciclib is 8.6 (6.5-11.1) months.
Conclusion
Elacestrant combinations show a consistent clinically meaningful PFS irrespective of ESR1 mutation status in patients with ER+/HER2– metastatic breast cancer after progressive disease on ET with or without prior CDK4/6i, and has the potential to become an ET backbone for combination strategies, supporting an all-oral approach that may delay the need for chemotherapy or antibody-drug conjugate–based regimens.
