Study design of the phase III ADELA trial of elacestrant with or without everolimus in ESR1-mutated ER+/HER2– advanced breast cancer after progression on endocrine therapy plus a CDK4/6 inhibitor

For patients with estrogen receptor-positive (ER+)/HER2-negative (HER2-) advanced breast cancer (aBC), endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i) is standard first-line treatment. However, ET resistance eventually develops, leading to disease progression. Mechanisms of endocrine resistance include PI3K/AKT/mTOR pathway constitutive activation and acquired mutations in the estrogen receptor 1 (ESR1) gene. Novel approaches are needed to improve outcomes for patients progressing on ET plus CDK4/6i. Elacestrant, a next-generation oral selective estrogen receptor degrader, is approved for patients with ER+/HER2- ESR1-mutated aBC after at least one line of ET, including a CDK4/6i. Everolimus, an mTORC1 inhibitor, is indicated in combination with exemestane for the treatment of postmenopausal women with ER+/HER2- aBC after progression on non-steroidal aromatase inhibitors. In the ELEVATE phase Ib/II trial, elacestrant plus everolimus showed a clinically meaningful progression-free survival (PFS) irrespective of ESR1 or PIK3CA mutation status in patients with ER+/HER2- aBC progressing after ET plus CDK4/6i. Here, we describe the design and methodology of ADELA, an international, multicenter, double-blind, placebo-controlled, randomized phase III trial evaluating elacestrant plus everolimus versus elacestrant plus placebo in patients with ER+/HER2-, ESR1-mutated aBC following ET plus CDK4/6i. The primary endpoint is PFS assessed by a blinded imaging review committee using RECIST v.1.1. www.clinicaltrials.gov identifier is NCT06382948; EU Clinical Trials identifier is EUCT 2024-512926-27-00. What type of study is this? ADELA is a global, multicenter, double-blind, placebo-controlled, randomized phase III trial. The study is designed to compare the efficacy of elacestrant combined with everolimus versus elacestrant with placebo. Who is eligible for this study? Patients who are eligible for the trial are women (premenopausal, perimenopausal, or postmenopausal) and men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Additionally, patients must have tumors with estrogen receptor 1 (ESR1) mutations and have experienced disease progression on prior treatment with endocrine therapy plus a CDK4/6 inhibitor. What is the study looking at? ER+/HER2− advanced breast cancer often initially responds well to endocrine therapy, but over time cancer cells may develop resistance, making the disease more difficult to control. More effective endocrine therapy-based options are needed for patients whose disease has progressed after endocrine therapy and CDK4/6 inhibitor. The ADELA study specifically focuses on those patients, evaluating whether combining two medicines that work in different ways may help control the disease for longer than current treatment approaches. The primary objective is to determine whether the combination of elacestrant and everolimus, compared with elacestrant plus placebo, can prolong progression-free survival, which is the length of time that patients remain alive without their cancer growing, spreading, or getting worse after starting study treatment. More information can be found at ClinicalTrials.gov by searching for NCT06382948 or at euclinicaltrials.eu by searching for EUCT 2024-512926-27-00.