Phase 2 Results From the ELEVATE Study: Elacestrant Combined With Everolimus or Abemaciclib in ER-Positive/HER2-Negative Locally Advanced or Metastatic Breast Cancer

Progression on 1L endocrine therapy (ET) plus CDK4/6 inhibitors in patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer is often driven by resistance mechanisms that diminish the efficacy of subsequent treatments. Current later-line options include ET with or without targeted agents such as CDK4/6 inhibitors or PI3K/AKT/mTOR pathway inhibitors, with clinical trials reporting median progression-free survival (PFS) ranging from 3.6 to 6.8 months for ET plus everolimus, and 5.3 to 9.4 months for CDK4/6 inhibitor switching. Elacestrant, an oral SERD, demonstrated significantly improved PFS versus standard-of-care ET in the EMERALD trial, with a hazard ratio of 0.55 in patients with ESR1-mutated tumors and 0.70 in all patients, alongside manageable safety. This article summarizes results from the phase 2 ELEVATE study, which evaluated combinations of elacestrant plus everolimus or elacestrant plus abemaciclib to address resistance mechanisms and improve outcomes across clinically relevant subgroups.

ELEVATE (NCT05563220) is an open-label, phase 2 umbrella study designed to evaluate elacestrant in combination with various targeted agents, including everolimus, abemaciclib, alpelisib, capivasertib, ribociclib, and palbociclib, for ER-positive/HER2-negative metastatic breast cancer. Eligible patients included those with 1 to 2 lines of prior ET regardless of ESR1 mutation status. Arm B (elacestrant plus everolimus) and arm C (elacestrant plus abemaciclib) required previous CDK4/6 inhibitor exposure, whereas arm D (elacestrant plus abemaciclib) enrolled patients without previous CDK4/6 inhibitor treatment. The primary objective was to assess PFS for elacestrant plus everolimus and elacestrant plus abemaciclib, with ESR1 and PIK3CA mutation status evaluated for subgroup analyses.

As of September 2025, 50 patients were enrolled in arm B (elacestrant plus everolimus), and 60 patients were enrolled in arms C and D (elacestrant plus abemaciclib, n=30 each). Baseline characteristics included a high proportion of patients with visceral metastases (72% in arm B, 92% in arms C/D), primary ET resistance (20% in arm B, 15% in arms C/D), ESR1 mutations (42% in arm B, 33% in arms C/D), and PIK3CA mutations (50% in arm B, 27% in arms C/D). Both combinations demonstrated consistent PFS benefits across subgroups, including patients with visceral metastases, no previous fulvestrant exposure, or no primary ET resistance. Elacestrant in combination with everolimus or abemaciclib showed clinically meaningful PFS. The median PFS in the elacestrant plus everolimus arm is 8.3 months, and in the elacestrant-plus- abemaciclib arm, the median PFS is 14.3 months. In arm B (elacestrant plus everolimus), the objective response rate (ORR) was 19.5%, stable disease (SD) was 63.4%, the disease control rate (DCR) was 82.9%, and median duration of response (mDOR) was 8.54 months. In arms C/D (elacestrant plus abemaciclib), ORR was 24.6%, SD was 66.7%, DCR was 91.2%, and mDOR was 14.75 months. Median follow-up for elacestrant plus abemaciclib was 8.6 months, with updated efficacy results expected. Elacestrant combinations showed safety profiles consistent with known profiles of everolimus or abemaciclib with standard ET. No bradycardia or photopia were reported, and there were low rates of drug withdrawal or dose reduction.

Elacestrant combinations demonstrated consistent PFS benefits regardless of ESR1 mutation status in patients with ER-positive/HER2-negative metastatic breast cancer who progressed on ET with or without previous CDK4/6 inhibitor exposure. These findings position elacestrant as a promising ET backbone for combination strategies with targeted agents, offering an all-oral treatment approach that may delay the need for chemotherapy or antibody–drug conjugates in this population.

Source: Rugo H, Tolaney SM, Chan N, et al. Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study. Presented at: San Antonio Breast Cancer Symposium 2025. December 11, 2025; San Antonio, TX. Presentation RF7-01.