ADELA: A double-blind, placebo-controlled, randomized phase 3 trial of elacestrant (Ela) + everolimus (EVE) versus elacestrant + placebo in ER+/HER2− advanced breast cancer (aBC) patients with <i>ESR1</i> -mutated tumors progressing on endocrine therapy (ET) + CDK4/6i.

Abstract

TPS1154 Background: ET+CDK4/6i is the standard-of-care (SOC) in 1L ER+/HER2- aBC; however, tumors eventually develop resistance. Constitutive activation of the PI3K/AKT/mTOR pathway can contribute to endocrine resistance in breast cancer. ESR1 mutations ( ESR1m ) are a common type of acquired resistance that emerges in 40-50% of patients (pts) in the metastatic setting after prolonged aromatase inhibitor exposure. There is an unmet need for novel therapeutic approaches to overcome resistance mechanisms and improve outcomes in pts with ER+/HER2- aBC with ESR1m tumors progressing after ET+CDK4/6i. Ela is a next-generation oral SERD that binds and degrades ERα. In the Ph3 EMERALD trial, single-agent Ela improved mPFS vs SOC ET in pts with ESR1m tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) [Bidard 2022]. Among pts who received prior ET+CDK4/6i ≥12 months, mPFS with Ela was 8.6 vs 1.9 months with SOC ET (HR 0.41; 95% CI 0.26-0.63) [Bardia 2024]. The crosstalk between the ER and PI3K/AKT/mTOR pathways provides a rationale for evaluating Ela+EVE (a mTORC1 inhibitor). In the ELEVATE Ph2 trial (NCT05563220), the combination of Ela 345 mg + EVE 7.5 mg showed a clinically meaningful mPFS of 8.3 months (95% CI, 4.0-10.2) in all pts (N=50) with ER+/HER2- aBC who progressed after ET+CDK4/6i, regardless of ESR1 m status (Rugo, SABCS 2025). Safety was consistent with the known profile of EVE+SOC ET. Methods: ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled, randomized Ph3 trial that compares Ela+EVE vs Ela+placebo in pts who have ER+/HER2- aBC with ESR1m tumors progressing on ET+CDK4/6i. Eligible pts are adults (≥18 years) with ER+/HER2- aBC and centrally confirmed ESR1m who received 1-2 prior lines of ET for aBC and progressed on ET+CDK4/6i for aBC after ≥6 months. Pts receiving CDK4/6i-based adjuvant therapy are eligible if progression occurred after ≥12 months of treatment but &lt;12 months following CDK4/6i completion. Exclusion criteria include prior chemotherapy for aBC and active uncontrolled/symptomatic brain metastases and/or leptomeningeal disease. Pts will be randomized 1:1 to 28-day cycles of Ela 345 mg + EVE 7.5 mg QD or Ela 345 mg + placebo QD until disease progression or unacceptable toxicity. Pts will receive dexamethasone mouthwash during the first 8 weeks. Stratification factors are visceral metastases (yes vs no) and duration of prior CDK4/6i therapy (≥12 vs &lt;12 months). Primary objective is PFS assessed by BICR. Secondary objectives are investigator-assessed OS, PFS, ORR, CBR, DoR, TTR, best percentage change in tumor burden, safety, HRQoL. Planned enrollment is 240 pts. Recruitment is ongoing across Spain, France, Greece, Italy, Germany, Austria, Czech Republic, United Kingdom, and Brazil. Clinical trial information: NCT06382948 .