Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment

ESR1 mutation (ESR1m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which is a first-line therapy for hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. SERENA-6 (NCT04964934) is a randomized, double-blind, phase III study evaluating the efficacy and safety of switching from an AI to camizestrant, while maintaining the same CDK4/6i, upon detection of ESR1m in circulating tumor DNA before clinical disease progression on first-line therapy for HR+/HER2- ABC. The aim is to treat ESR1m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.Why will we perform this study? Patients with advanced breast cancer in which the cancer cells have the receptor for the hormone estrogen and/or progesterone are typically treated with an aromatase inhibitor, a hormone therapy that decreases estrogen being made in the body, together with an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), a drug that blocks the growth of cancer cells. Although cancers usually respond to treatment initially, the cancer cells eventually change, so the drug combination no longer works. For example, mutation of the estrogen receptor (referred to as ESR1m) can stop aromatase inhibitors from working. Camizestrant is an investigational drug that blocks estrogen receptors, including mutated receptors, reducing the growth and spread of cancer. Here we describe the SERENA-6 clinical trial, which is testing camizestrant as a treatment for patients with breast cancer with ESR1m. How will we perform this research? The phase III SERENA-6 trial will use blood tests to monitor if patients with breast cancer develop ESR1m while being treated with an aromatase inhibitor and a CDK4/6 inhibitor. If ESR1m is detected, yet the disease is stable, participants will be randomly assigned to either continue with the same aromatase inhibitor or switch to camizestrant while continuing with the same CDK4/6 inhibitor. The study will assess whether switching to camizestrant prolongs the time before the cancer grows, spreads or worsens. It will also assess the length of time that participants live for versus those who continue with an aromatase inhibitor. Clinical Trial Registration: NCT04964934 (ClinicalTrials.gov).