Real-world comparative safety and survival of alpelisib-fulvestrant versus capivasertib-fulvestrant in HR+/HER2− metastatic breast cancer: A propensity score–matched analysis.

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Background: Alpelisib (PI3Kα inhibitor) and capivasertib (AKT inhibitor), each combined with fulvestrant, are approved options for PIK3CA/AKT pathway–altered HR+/HER2− metastatic breast cancer (MBC) after CDK4/6 inhibitor (CDK4/6i) progression. An indirect treatment comparison using SOLAR-1 and CAPItello-291 data suggested favorable PFS and safety for capivasertib-fulvestrant (CF), but no real-world head-to-head comparison exists. We conducted the first direct real-world comparative analysis of alpelisib-fulvestrant (AF) versus CF. Methods: Using the TriNetX Global Collaborative Network (171 HCOs), we identified adults with MBC (C50 + C77–C79) who initiated AF or CF, with fulvestrant within 30 days of the index drug. Propensity score matching (1:1) balanced cohorts on age, sex, race, metastatic sites, Charlson comorbidities, pre-existing diabetes, and baseline labs. Outcomes included overall survival (OS) and safety endpoints assessed via Kaplan-Meier and risk analyses. Results: After matching, 315 patients per cohort were analyzed. Median follow-up was 509 (AF) vs 251 (CF) days. OS did not differ significantly (HR 1.295; 95% CI 0.975–1.721; p=0.073). AF was associated with significantly higher metabolic, mucocutaneous toxicity, and healthcare utilization. Diarrhea, nausea, and hepatotoxicity were comparable. Conclusions: In this first real-world head-to-head comparison, AF and CF showed comparable OS, but AF was associated with significantly greater metabolic toxicity, stomatitis, ED utilization, fatigue, and weight loss. These findings complement trial-based indirect comparisons and support a more favorable real-world safety profile of CF, informing shared treatment decisions in post-CDK4/6i PIK3CA-mutated MBC.

Safety outcomes after propensity score matching.