Safety profile of aromatase inhibitors combined with CDK4/6 inhibitors: a real-world analysis based on FAERS

Abstract Background The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) is now a cornerstone first-line treatment. However, the comprehensive safety profile of this combination has not been fully characterized. The aim of this study was to evaluate the real-world safety profile of AIs combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in advanced breast cancer from the US FDA Adverse Event Reporting System (FAERS). Methods A retrospective pharmacovigilance study was conducted using FAERS data from 2015 to 2024. Disproportionality analyses were performed using four established algorithms (ROR, PRR, BCPNN, and MGPS) to detect safety signals for adverse events (AEs) at the System Organ Class (SOC) and Preferred Term (PT) levels. The time to onset (TTO) of AEs was analyzed using the Kruskal‒Wallis test, and risk factors for important medical events (IMEs) were identified via logistic regression. Results Among 19,746 patients treated with AIs, 3,739 (18.9%) received combination therapy. The analysis revealed a distinct AE profile for combination therapy, with hematological toxicity being the most prominent. Strong, consistent signals were detected for neutropenia (ROR = 143.57), anemia, and thrombocytopenia. Compared with AI monotherapy (60–90 days), combination therapy was associated with a significantly delayed median TTO of AEs (> 180 days) ( P < 0.001), with significant variation among specific drug pairs. Logistic regression revealed older age (OR = 1.022 per year; P = 0.0003) and anastrozole use (vs. letrozole; OR = 1.876; P = 0.004) as independent risk factors for IMEs. Compared with abemaciclib, ribociclib (OR = 0.299; P < 0.001) and palbociclib (OR = 0.595; P = 0.012) were associated with a significantly lower risk of IMEs. Discussion This large-scale real-world analysis confirms the significant hematological toxicity of the AI and CDK4/6 inhibitor combination therapy and reveals a previously underappreciated delay in AE onset. Conclusion This study reveals that the risk of serious outcomes is not uniform but is significantly influenced by patient age and the specific choice of AI and CDK4/6 inhibitor, underscoring the need for a personalized, risk-adapted approach to treatment selection and monitoring.