Mechanism-driven comparative safety signals of capivasertib versus CDK4/6 inhibitors: A FAERS pharmacovigilance study.

Abstract

e23444 Background: Capivasertib, a first-in-class AKT inhibitor approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer, exhibits a toxicity profile distinct from cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Post-marketing pharmacovigilance offers an opportunity to characterize real-world safety patterns beyond clinical trials. We compared adverse event (AE) reporting profiles of capivasertib and CDK4/6 inhibitors using the FDA Adverse Event Reporting System (FAERS). Methods: FAERS reports from 2011-2026 were queried for capivasertib and CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib). AEs of interest were grouped according to the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analyses were performed using reporting odds ratios (RORs) with 95% confidence intervals (CIs) calculated from 2×2 contingency tables, with statistical significance evaluated using chi-square testing (1 df). Results: A total of 2,112 capivasertib reports and 137,831 CDK4/6 inhibitor reports were identified. Capivasertib demonstrated striking enrichment of metabolic toxicities consistent with AKT-pathway inhibition, including hyperglycemia (ROR 62.23; 95% CI 51.53–75.14; p < 1×10⁻¹⁰) and diabetic ketoacidosis (ROR 120.54; 95% CI 79.06–183.77; p < 1×10⁻¹⁰). Dermatologic immune-mediated events were also significantly over-reported, including rash (ROR 6.07; 95% CI 5.36–6.88; p < 1×10⁻¹⁰) and erythema multiforme (ROR 64.40; 95% CI 43.90–94.49; p < 1×10⁻¹⁰). Gastrointestinal AEs demonstrated a heterogeneous pattern, with increased diarrhea reporting (ROR 1.79; 95% CI 1.59–2.01; p < 0.001) but reduced nausea reporting (ROR 0.55; 95% CI 0.45–0.66; p < 0.001). In contrast, capivasertib was associated with markedly lower hematologic toxicity compared with CDK4/6 inhibitors, including neutropenia (ROR 0.04), leukopenia (ROR 0.02), and thrombocytopenia (ROR 0.20), all p < 0.001. A mortality signal was observed for capivasertib (ROR 1.76; 95% CI 1.56-2.00; p < 0.001), though interpretation is limited by confounding from disease severity, prior therapy exposure, and inherent FAERS reporting bias. Conclusions: Capivasertib exhibited a distinct toxicity signature characterized by pronounced metabolic and dermatologic adverse events and substantially lower hematologic toxicity compared with CDK4/6 inhibitors. These findings align with the drug’s mechanism of AKT inhibition and underscore the importance of proactive metabolic monitoring and early dermatologic management in clinical practice. Prospective and comparative real-world studies are warranted to contextualize the observed mortality signal and refine patient selection.