OPERA-01: a phase III study of palazestrant for ER+, HER2- advanced breast cancer after CDK4/6 inhibitor therapy.

Endocrine therapy (ET) resistance is a major concern when treating estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. A combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and ET is the current first-line standard of care (SOC) for patients with ER+, HER2- advanced breast cancer. Despite the benefits of ET plus a CDK4/6i, disease progression due to endocrine resistance remains a significant challenge. More effective ETs that can overcome resistance are needed to improve clinical outcomes and maintain quality of life by delaying chemotherapy. Palazestrant is a novel oral, complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that blocks both transcriptional activation function domains, AF1 and AF2, resulting in complete inhibition of ER-driven transcription, regardless of estrogen receptor 1 (ESR1) mutation status. As monotherapy, palazestrant showed tolerable safety, favorable pharmacokinetics, and antitumor efficacy in heavily pretreated patients during phase I/II studies. OPERA-01 (NCT06016738) is a phase III study designed to evaluate the safety and efficacy of palazestrant monotherapy compared to SOC ET in patients with ER+, HER2- locally advanced or metastatic breast cancer, regardless of ESR1 mutation status, whose disease advanced following treatment with at least one ET in combination with a CDK4/6i.Clinical Trial Registration: Clinicaltrials.gov NCT06016738. Registered 17 August 2023.