Elacestrant in combination with capivasertib in patients with ER+/HER2− advanced breast cancer: Update from ELEVATE, a phase 1b/2, open-label, umbrella study.

Abstract

1098 Background: Disease progression in patients (pts) with ER+/HER2- ABC on 1L ET+CDK4/6i is associated with several mechanisms of resistance, including intrinsic alterations in the PI3K/AKT/mTOR or cell cycle pathways, and/or ESR1 mutations, a type of acquired resistance that emerges in up to 50% of pts. Elacestrant is the only single-agent oral SERD to significantly improve PFS vs SOC ET in all pts (HR 0.70; 95% CI 0.55-0.88; P=0.0018) and in those with ESR1m tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) with manageable safety in EMERALD, a trial that required prior ET+CDK4/6i [Bidard 2022]. In CAPItello-291, capivasertib + fulvestrant showed a mPFS of 7.3 mo (AKT-pathway altered) and 5.5 mo (prior CDK4/6i exposure) [Turner 2023]. In ER+ BC MCF7 CDX and CTG-2308 PDX models ( ESR1 wt/ PIK3CAm ), elacestrant + capivasertib showed superior antitumor activity compared with single-agent treatment, including an improvement in activity vs fulvestrant + capivasertib, further supporting the rationale to combine elacestrant with an AKT inhibitor in ER+ BC [Data on file]. This analysis reports updated Ph 1b safety and preliminary efficacy for elacestrant + capivasertib. Methods: ELEVATE is evaluating elacestrant in combination with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib to address different resistance mechanisms. Pts with ER+/HER2- ABC and 1-2L of prior ET±CDK4/6i are eligible regardless of ESR1m status; no prior chemo allowed in the ABC setting. Objectives are to identify the RP2D (Ph 1b) and evaluate PFS (Ph 2). Results: As of Dec 2025, 31 pts have been enrolled in the Ph 1b elacestrant (258-345 mg) + capivasertib (320-400 mg) cohorts. Key baseline characteristics include pts with visceral mets (90%), primary endocrine resistance (23%), ESR1m (45%), prior CDK4/6i (94%), and prior fulvestrant (45%). The most common (≥35%) TEAEs were diarrhea (81%; 6% Gr 3), nausea (74%; 0% Gr 3), rash (61%; 13% Gr 3), fatigue (58%; 3% Gr 3), vomiting (42%; 0% Gr 3); observed hyperglycemia was 29% (10% Gr 3). Elacestrant 345 mg QD + capivasertib 320 BID [4 days on/3 days off] was determined as the RP2D based on the safety profile and PK analysis; no DLTs were observed. In RP2D response-evaluable pts (n=9), preliminary efficacy showed an ORR of 22%, CBR24 wk at 67% (1 CR, 1 PR, and 6 SD), and a mPFS of 11.3 mo. Median follow-up is 10.2 mo [1.8-12.0]. Updated results and additional data will be reported. Conclusions: Elacestrant + capivasertib shows a manageable safety profile, consistent with known capivasertib + fulvestrant Gr 3 AEs, and clinically important efficacy in pts with AKT-pathway altered ER+/HER2- ABC with progressive disease. Enrollment in Ph 2 is ongoing. Elacestrant + capivasertib combination therapy offers pts the benefit of receiving both drugs with manageable safety and potential extended clinical benefit as an all-oral treatment option. Clinical trial information: NCT05563220 .