The ADELA Study: Elacestrant Plus Everolimus Versus Elacestrant Plus Placebo in ER-Positive/HER2-Negative Advanced Breast Cancer With ESR1 Mutations After Progression on Endocrine Therapy and CDK4/6 Inhibitors

Endocrine therapy (ET) combined with CDK4/6 inhibitors is the standard of care for 1L treatment of estrogen receptor (ER)-positive/HER2-negative advanced breast cancer. However, tumors inevitably develop resistance, often driven by mechanisms such as constitutive activation of the PI3K/AKT/mTOR pathway. ESR1 mutations, a common form of acquired resistance, emerge in 4% to 50% of patients in the metastatic setting after prolonged aromatase inhibitor exposure. This highlights the unmet need for novel therapeutic strategies to overcome resistance and improve outcomes in patients with ER-positive/HER2-negative and ESR1-mutated tumors following progression on an ET-positive CDK4/6 inhibitor. Elacestrant, a next-generation oral SERD, binds to ER-alpha and induces its degradation. This article describes the ADELA trial that was initiated to evaluate elacestrant plus everolimus versus elacestrant plus placebo in this patient population.

ADELA (NCT06382948) is a global, multicenter, double-blind, placebo-controlled phase 3 trial designed to assess the efficacy and safety of elacestrant plus everolimus versus elacestrant plus placebo in patients with ER-positive/HER2-negative advanced breast cancer and centrally confirmed ESR1 mutations. Eligible patients include adults aged ≥18 years who have received 1 to 2 previous lines of ET for advanced breast cancer and have evidence of disease progression on ET-positive CDK4/6 inhibitors after ≥6 months. Patients treated with CDK4/6 inhibitor–based adjuvant therapy are eligible if disease progression occurred ≥12 months after treatment but <12 months following CDK4/6 inhibitor completion. Key inclusion criteria include adequate organ function, an ECOG Performance Status of 0 to 1, and no previous use of elacestrant or similar agents (SERDs, PROTACs, CERANs, novel SERMs, or PI3K/AKT/mTOR inhibitors). Exclusion criteria include formal contraindication to ET defined as visceral crisis and/or rapidly or symptomatic progressive visceral disease and received treatment with approved or investigational cancer therapy ≤14 days prior to randomization (except for fulvestrant that must be completed ≥28 days before randomization), prior chemotherapy for advanced breast cancer and active uncontrolled or symptomatic central nervous system metastases, metastasis-related spinal cord compression, and/or leptomeningeal disease. Patients will be randomized 1:1 to receive 28-day cycles of 345 mg oral elacestrant plus 7.5 mg everolimus daily, or 345 mg elacestrant plus placebo daily until disease progression or unacceptable toxicity. Dexamethasone mouthwash will be administered during the first 8 weeks. Stratification factors include visceral metastases (yes vs no) and duration of prior CDK4/6 inhibitor therapy (≥12 vs <12 months) in the advanced setting.

The primary endpoint is progression-free survival (PFS) assessed by a blinded independent review committee. Secondary endpoints include investigator-assessed PFS, overall survival as determined locally by investigator, investigator-assessed objective response rate, clinical benefit rate, duration of response, time to response, best percentage change in tumor burden, safety, and health-related quality of life.

ADELA trial aims to enroll 240 patients, and recruitment is currently ongoing across multiple international sites, including Spain, France, Greece, Italy, Germany, Austria, the Czech Republic, the United Kingdom, and Brazil.

Source: Llombart-Cussac A, Pérez-García JM, Lopez-Miranda E, et al. 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. Presented at: San Antonio Breast Cancer Symposium 2025. December 10, 2025; San Antonio, TX. Presentation PS1-11-02.