Abstract PS1-11-02: The ADELA study: a double-blind, placebo-controlled, randomized phase 3 trial of elacestrant + everolimus versus elacestrant + placebo in ER+/HER2- advanced breast cancer (ABC) patients with ESR1-mutated tumors progressing on endocrine therapy (ET) + CDK4/6i

Abstract 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 are a common type of acquired resistance that emerges in 40-50% of patients 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 patients with ER+/HER2- ABC with ESR1-mutated tumors progressing after ET+CDK4/6i. Elacestrant is a next-generation oral SERD that binds to ER-alpha, inducing its degradation. In the EMERALD study, single-agent elacestrant improved PFS vs SOC ET in patients with ESR1-mutated tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) [Bidard 2022]. Differences were notable among patients who received prior ET+CDK4/6i ≥12 months; median PFS with elacestrant 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 elacestrant+everolimus (a mTORC1 inhibitor). In the ELEVATE phase 1b trial (NCT05563220), the combination of elacestrant and everolimus demonstrated a median PFS of 8.3 months (95% CI, 3.9 to NR) in all patients (N=23) with ER+/HER2- ABC who progressed after ET+CDK4/6i, regardless of ESR1-mutation status (Rugo, ASCO 2025); elacestant 345 mg + everolimus 7.5 mg was identified as the RP2D [Rugo ESMO 2024]. Safety was consistent with the known profile of everolimus+SOC ET. The ADELA study compares elacestrant+everolimus vs elacestrant+placebo in ER+/HER2- ABC patients with ESR1-mutated tumors progressing on ET+CDK4/6i. Design and Methods: ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled phase 3 trial. Eligible patients are adults (≥18 years) with ER+/HER2- ABC and centrally confirmed ESR1 mutations, previously treated with 1-2 lines of ET for ABC, and evidence of disease progression on prior ET+CDK4/6i for ABC after ≥6 months. Patients receiving CDK4/6i-based adjuvant therapy are eligible provided that disease progression is confirmed after ≥12 months of treatment but <12 months following CDK4/6i completion. Other criteria include adequate organ function, ECOG PS 0-1 and no prior use of elacestrant or other SERDs, PROTAC, CERAN, or novel SERM, and/or PI3K/AKT/mTOR inhibitors. Exclusion criteria include prior chemotherapy for ABC and active uncontrolled/symptomatic brain metastases and/or leptomeningeal disease. Patients will be randomized 1:1 to 28-day cycles of oral elacestrant 345 mg + everolimus 7.5 mg QD or elacestrant 345 mg + placebo QD until disease progression or unacceptable toxicity. Patients will receive dexamethasone mouthwash during the first 8 weeks. Stratification factors are presence of visceral metastases (yes vs no) and duration of prior CDK4/6i therapy (≥12 vs <12 months). The primary objective is to evaluate PFS assessed by blinded independent review committee. Secondary endpoints include investigator-assessed PFS, OS, ORR, CBR, DoR, TTR, best percentage change in tumor burden, safety, and HRQoL. Status: Planned enrollment is 240 patients. Rrecruitment is ongoing across Spain, France, Greece, Italy, Germany, Austria, Czech Republic, United Kingdom, and Brazil. Citation Format: A. Llombart-Cussac, J. M. Pérez-García, E. Lopez-Miranda, C. Saavedra, V. Carañana, I. Blancas, C. Hinojo, A. Cortes-Salgado, E. Galve-Calvo, R. R. Zhang, M. Sampayo-Cordero, D. Alcalá-López, J. Carvalho-Santos, O. Boix, A. Garrido, C. H. Barrios, G. Curigliano, R. Bartsch, A. Hardy-Bessard, T. Wasserman, J. Cortés. The ADELA study: a double-blind, placebo-controlled, randomized phase 3 trial of elacestrant + everolimus versus elacestrant + placebo in ER+/HER2- advanced breast cancer (ABC) patients with ESR1-mutated tumors progressing on endocrine therapy (ET) + CDK4/6i [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-11-02.