Comparative neurological safety of novel hormonal therapies in advanced prostate cancer: a Bayesian network meta-analysis of randomized trials.

Background: Novel hormonal agents (NHAs), including enzalutamide, abiraterone acetate, apalutamide, and darolutamide, have improved survival in advanced prostate cancer (PCa). However, their potential neurological adverse effects (AEs)-notably cognitive impairment, seizures, and falls-raise safety concerns, particularly in older adults. This study aimed to compare the neurological safety profiles of NHAs in men with advanced PCa using a Bayesian network meta-analysis (NMA).

Methods: We conducted a systematic review and Bayesian NMA following PRISMA-NMA guidelines. Comprehensive searches of PubMed, EMBASE, and Web of Science were completed through May 21, 2025. Eligible randomized controlled trials (RCTs) compared NHAs plus androgen deprivation therapy (ADT) with placebo, ADT, or other NHAs. Neurological AEs of interest included cognitive impairment, falls, and seizures. Bayesian random-effects models were used to calculate risk ratios (RRs) with 95% credible intervals (CrIs). Treatments were ranked using surface under the cumulative ranking curve (SUCRA) values.

Results: Twenty-five RCTs with over 19,000 patients were included. No treatments showed a statistically significant increased risk of neurological AEs. Enzalutamide had the highest estimated risk for cognitive impairment (RR 3.88; 95% CrI, 0.697-22.1) and seizures (RR 13.8; 95% CrI, 0.983-1.07 × 10³), although not statistically significant. Darolutamide and nonsteroidal antiandrogens exhibited the most favorable neurological safety profiles across outcomes based on SUCRA rankings.

Conclusion: Although no NHA significantly increased neurological AEs, enzalutamide showed the highest estimated risk, while darolutamide and NSAAs ranked best for neurological safety. Darolutamide may be preferred in elderly patients, highlighting the need for further long-term safety data.