BMC Cancer. 2026 May 23. doi: 10.1186/s12885-026-16146-4. Online ahead of print.
ABSTRACT
OBJECTIVE: Androgen receptor pathway inhibitors (ARPIs) are cornerstone treatments for advanced prostate cancer; however, their potential to increase fall risk remains a significant clinical concern. This meta-analysis aims to provide a rigorous, drug-specific evaluation of the association between novel ARPIs and the risk of falls.
METHODS: We systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov for Phase 2 or 3 randomized controlled trials (RCTs) comparing ARPIs (enzalutamide, apalutamide, and darolutamide) with control groups (placebo or non-steroidal antiandrogens [NSAA]). The primary outcomes were risk ratios (RRs) for all-grade and grade ≥ 3 falls. To account for multiplicity across correlated outcomes and the limited number of studies, pooled RRs were estimated using random-effects models with the restricted maximum-likelihood (REML) method. All analyses were performed on a logarithmically transformed scale, with 97.5% confidence intervals (CIs). Prediction intervals (PIs) were calculated to assess the dispersion of effects. Subgroup analyses were stratified by specific ARPI agents, control types, and clinical stages.
RESULTS: Eleven RCTs involving 12,239 patients were included. Overall, ARPIs were significantly associated with the increased risk of all-grade falls (RR 2.00, 97.5% CI 1.46-2.73, P < 0.0001, I2 = 77.6%; PI 0.67-5.99) and grade ≥ 3 falls (RR 2.15, 97.5% CI 1.32-3.52, P = 0.0008, I2 = 0%; PI 1.15-4.02). However, risk profiles varied substantially across individual agents. Enzalutamide was associated with the highest risk increase (RR 2.55 vs. placebo, 97.5% CI 1.62-4.01, I2 = 79.2%; RR 2.47 vs. NSAA, 97.5% CI 1.14-5.37, I2 = 71.8%), followed by apalutamide (RR 1.65, 97.5% CI 0.77-3.52, I2 = 87.2%). In contrast, darolutamide demonstrated a favorable safety profile with no statistically significant increase in the risk of all-grade falls (RR 1.25, 97.5% CI 0.87-1.79, I2 = 0%) or severe falls (RR 1.31, 97.5% CI 0.34-5.00).
CONCLUSIONS: Current evidence indicates that the increased risk of falls associated with ARPI therapy varies significantly among individual agents, rather than being a uniform class effect. While enzalutamide and apalutamide are statistically associated with elevated fall risk, darolutamide appears to maintain a more favorable safety profile. However, these drug-specific comparisons remain exploratory due to subgroup imbalances. Clinicians should consider proactive fall-risk assessments and individualized treatment selection, particularly for elderly or frail populations.
PMID:42177476 | DOI:10.1186/s12885-026-16146-4
