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.Clinical trial registration www.clinicaltrials.gov identifier is NCT06382948; EU Clinical Trials identifier is EUCT 2024-512926-27-00.