Safety of CDK4/6 inhibitors in older patients: A FAERS-based analysis of serious and fatal adverse events.

[INTRODUCTION] CDK4/6 inhibitors-abemaciclib, palbociclib, and ribociclib-are standard treatments for hormone receptor-positive, ERBB2 (HER2)-negative metastatic breast cancer. However, older adults are underrepresented in clinical trials, and age-related safety data remain limited in real-world settings.

[MATERIALS AND METHODS] We conducted a pharmacovigilance analysis using 44,100 individual case safety reports (ICSRs) from the FDA Adverse Event Reporting System (FAERS) involving patients aged ≥65 years treated with CDK4/6 inhibitors. Primary endpoints included serious adverse events (SAEs) and fatal outcomes. A secondary analysis compared adverse events between patients aged <65 and 65-85 years, calculating odds ratios (ORs) for selected toxicities, including death, disease progression, diarrhea, and myelosuppression.

[RESULTS] Among older patients, 71.2 % of reports involved SAEs and 5.3 % were fatal. Abemaciclib was linked to higher risk of death in those aged 65-85 compared to younger adults (OR 1.53; 95 % CI 1.18-1.99), but lower odds of myelosuppression (OR 0.37; 95 % CI 0.26-0.53). Palbociclib showed similar death risk across age groups (OR 0.98; 95 % CI 0.92-1.05) and reduced risk of disease progression in older adults (OR 0.72; 95 % CI 0.61-0.84). Ribociclib showed no significant age-related difference in fatality (OR 1.01; 95 % CI 0.87-1.17) but had the highest overall death risk (OR 9.14 vs palbociclib; 95 % CI 7.70-10.84).

[DISCUSSION] Real-world data reveal drug- and age-specific toxicity differences. Ribociclib and abemaciclib pose higher risks in older adults compared to palbociclib, supporting the need for personalized treatment and careful monitoring in older patients.