Systematic review and meta-analysis of comparative fall risk of prostate cancer patients receiving novel androgen receptor antagonists

Androgen receptor pathway inhibitors (ARPIs) are cornerstone treatments for advanced prostate cancer; however, their potential to increase fall risk remains a significant clinical concern. A systematic review and meta-analysis of published phase 2 and 3 randomized controlled trials (RCTs) evaluated drug-specific association of novel ARPIs and risk of falls. Eleven RCTs involving 12,239 patients, comparing ARPIs (enzalutamide, apalutamide, and darolutamide) with control (placebo or non-steroidal antiandrogens) were included. Primary outcomes were risk ratios (RRs) for all-grade and grade ≥ 3 falls. Overall, ARPIs were significantly associated with increased risk of all-grade falls (RR 2.00; 97.5% CI 1.46-2.73; I²=77.6%) and grade ≥ 3 falls (2.15; 1.32-3.52; 0%); however, risk profiles varied substantially across individual agents. Enzalutamide was associated with the highest risk increase, followed by apalutamide. In contrast, darolutamide demonstrated a favorable safety profile, with no statistically significant increase in the risk of all-grade falls and grade ≥ 3 falls. The authors conclude that the increased risk of falls associated with ARPI therapy varies significantly among individual agents, rather than being a uniform class effect.