Background
Endocrine therapy (ET) plus CDK4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) in first-line estrogen receptor–positive (ER+/HER2-negative (HER2–) advanced breast cancer; 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% to 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– advanced breast cancer with ESR1-mutated tumors progressing after ET plus CDK4/6i. Elacestrant is a next-generation oral SERD that binds and degrades ERα. In the phase 3 EMERALD trial, single-agent elacestrant improved median progression-free survival (PFS) vs SOC ET in patients with ESR1-mutated tumors (HR, 0.55; 95% CI, 0.39-0.77; P = .0005). Among patients who received prior ET plus CDK4/6i for 12 months or more, median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (HR, 0.41; 95% CI, 0.26-0.63). The crosstalk between the ER and PI3K/AKT/mTOR pathways provides a rationale for evaluating elacestrant+everolimus (an mTORC1 inhibitor). In the ELEVATE phase 2 trial (NCT05563220), the combination of elacestrant 345 mg plus everolimus 7.5 mg showed a clinically meaningful median PFS of 8.3 months (95% CI, 4.0-10.2) in all patients (n = 50) with ER+/HER2– advanced breast cancer who progressed after ET plus CDK4/6i, regardless of ESR1 mutation status. Safety was consistent with the known profile of everolimus plus SOC ET.
Design and Methods
ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled, randomized phase 3 trial that compares elacestrant plus everolimus vs elacestrant plus placebo in patients who have ER+/HER2– advanced breast cancer with ESR1-mutated tumors progressing on ET plus CDK4/6i. Eligible patients are adults (≥18 years) with ER+/HER2– advanced breast cancer and centrally confirmed ESR1 mutations who received 1 to 2 prior lines of ET for advanced breast cancer and progressed on ET plus CDK4/6i for advanced breast cancer after ≥6 months. Patients receiving CDK4/6i-based adjuvant therapy are eligible if progression occurred after 12 months or more of treatment but less than 12 months following CDK4/6i completion. Exclusion criteria include prior chemotherapy for advanced breast cancer and active uncontrolled/symptomatic brain metastases and/or leptomeningeal disease. Patients will be randomly assigned 1:1 to 28-day cycles of elacestrant 345 mg plus everolimus 7.5 mg once daily or elacestrant 345 mg plus placebo once daily until disease progression or unacceptable toxicity. Patients will receive dexamethasone mouthwash during the first 8 weeks. Stratification factors include visceral metastases (yes vs no) and duration of prior CDK4/6i therapy (≥12 vs <12 months). Primary objective is PFS assessed by blinded independent central review. Secondary objectives include investigator-assessed PFS, overall survival, overall response rate, clinical benefit rate, duration od response, time to response, best percentage change in tumor burden, safety, and health-related quality of life.
Status
Planned enrollment is 240 patients. Recruitment is ongoing across Spain, France, Greece, Italy, Germany, Austria, Czech Republic, United Kingdom, and Brazil.
