Safety Profile Comparison of Androgen Receptor Pathway Inhibitors: A Pharmacovigilance Signal Detection Analysis...

Androgen receptor pathway inhibitors (ARPIs) are prescribed across heterogeneous prostate cancer disease states, so direct comparison of adverse event reporting frequencies risks confounding by indication. We applied disproportionality signal detection and age-stratified comparisons to identify differential reporting signals across four ARPIs in the FDA Adverse Event Reporting System (FAERS).

We analyzed 37,875 ARPI monotherapy reports (Q1 2004-Q4 2025; accessed January 14, 2026): enzalutamide (n = 29,419), apalutamide (n = 4884), darolutamide (n = 2236), abiraterone (n = 1336). Primary analyses comprised reporting proportion comparisons and disproportionality detection using Reporting Odds Ratios (ROR) and Proportional Reporting Ratios (PRR) with Evans criteria (PRR ≥ 2.0, lower 95% CI > 1.0, n ≥ 3), with Benjamini-Hochberg FDR correction across 24 comparisons. Secondary analyses included age stratification (< 65, 65-75, > 75 years) and multivariate logistic regression (drug, age, reporter type, report year, country).

Strong signals: apalutamide rash/skin reactions (PRR 4.25, 95% CI 3.91-4.62; ROR 4.87; n = 791) and darolutamide neuropathy (PRR 4.90, 4.00-6.01; ROR 5.12; n = 116), the latter likely confounded by concurrent docetaxel. Moderate signals: abiraterone hospitalization (PRR 1.75, 1.64-1.88) and enzalutamide fatigue/asthenia (PRR 1.58, 1.49-1.67). Death was reported in 24.12% of enzalutamide versus 11.23% of abiraterone cases, a difference highly susceptible to confounding by indication and not causally interpretable.

This FAERS analysis identifies hypothesis-generating differential adverse event reporting signals across ARPIs. Findings are exploratory, require prospective validation, and should not be used to establish causal drug effects or comparative safety conclusions.