Interstitial pneumonia signals of apalutamide, darolutamide, and enzalutamide in FAERS and JADER

Abstract

Background Apalutamide, darolutamide, and enzalutamide are widely used androgen receptor signaling inhibitors (ARSIs) for prostate cancer. Although their clinical benefits are established, interstitial pneumonia remains an uncommon but potentially serious pulmonary adverse event that is insufficiently characterized in routine practice. Methods We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER). Reports listing apalutamide, darolutamide, or enzalutamide as the primary or suspected drug were identified after drug-name standardization. Interstitial pneumonia/interstitial lung disease was defined at the preferred-term level. Reporting odds ratio (ROR) analysis was used for signal detection; a positive signal was defined as at least three reports and a lower 95% confidence interval of the ROR greater than 1. Time-to-onset patterns were assessed using monthly and cumulative reporting proportions and Weibull distribution analysis. Results After data cleaning, 59, 603 target-drug reports were identified in FAERS and 4, 812 in JADER. In FAERS, interstitial lung disease showed positive disproportionality signals for all three ARSIs, with the strongest signal for darolutamide, followed by apalutamide and enzalutamide. In JADER, positive signals were observed for apalutamide and darolutamide, whereas enzalutamide did not meet the predefined signal criterion. Weibull analysis suggested a random-failure pattern for apalutamide in both databases. Darolutamide showed a wear-out pattern in FAERS and a random-failure pattern in JADER. Enzalutamide showed a consistent early-failure pattern in both databases. Conclusion The three ARSIs showed heterogeneous interstitial pneumonia reporting patterns in FAERS and JADER. Apalutamide and darolutamide demonstrated more consistent disproportionality signals, whereas enzalutamide showed weaker signal strength but a reproducible early-onset pattern among reports with valid time-to-onset information. These findings support continued pharmacovigilance and early clinical monitoring, while recognizing that spontaneous reporting signals cannot establish causality or true incidence.