SERENA-6 Phase 3 Trial: Camizestrant Plus CDK4/6 Inhibitor for ctDNA-Guided Treatment of ESR1 Mutations in HR-Positive, HER2-Negative Advanced Breast Cancer

The SERENA-6 trial investigated the clinical efficacy of camizestrant, a next-generation selective estrogen receptor degrader and complete estrogen receptor antagonist, in combination with a CDK4/6 inhibitor for patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). The study focused on patients who developed ESR1 mutations (ESR1m), a common mechanism of resistance to aromatase inhibitors (AIs) and CDK4/6i therapy during first-line treatment. Patients with HR-positive, HER2-negative ABC and who had received ≥6 months of AI and CDK4/6i therapy were enrolled. ESR1m was detected using regular molecular monitoring through circulating tumor DNA (ctDNA) analysis every 2 to 3 months. Patients without disease progression at the time of ESR1m detection were randomized to either camizestrant (75 mg) plus a CDK4/6i or continued AIs plus a CDK4/6i.

The trial screened 3256 patients for ESR1m surveillance, of which 315 were randomized to either of the 2 arms. Camizestrant significantly improved progression-free survival (PFS) as seen in the Table. Benefits were consistent across subgroups. Secondary endpoint analysis of PFS2 at a 27% maturity also favored camizestrant. Camizestrant in combination with CDK4/6i was well tolerated, with safety profiles aligning with prior studies; treatment discontinuation due to adverse events was low for both arms (1-2%).

As the first global Phase 3 trial to demonstrate the clinical utility of ctDNA-guided therapy toward identifying and treating resistance, SERENA-6 highlights the promise of camizestrant in addressing ESR1m resistance before disease progression. These findings suggest a paradigm shift in managing HR-positive, HER2-negative ABC, offering a potential new treatment strategy to optimize and extend patient outcomes in the first-line setting.

Source: Turner N, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): phase 3, double-blind ctDNA-guided SERENA-6 trial. Presented at: 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract LBA4.