Seizures And Neuropsychiatric Toxicity In Patients With Non-Metastatic Crpc Treated With New Antiandrogens: Systematic Review And Meta-Analysis

Introduction: Recently, enzalutamide, apalutamide, and darolutamide have shown benefits in metastasis-free survival in non-metastatic castration-resistant prostate cancer (nmCRPC) patients compared to placebo. Previous evidence about the safety profile of these new androgens is limited. This meta-analysis studies seizure and neuropsychiatric effects of new anti-androgens compared to placebo in nmCRPC patients. Methods: PubMed and Cochrane databases were systematically reviewed until 1 March 2020 by 2 independent researchers using a pre-specified search strategy. Placebo-compared randomized controlled trials (RCTs) of nmCRPC patients treated with new anti-androgens providing data on neuropsychiatric events and seizures were included. Variables were seizure, headache, mental impairment, and dizziness. Pooled risk ratios (RR) were calculated using the Mantel-Hansel random effects model and Review Manager v5.3 software. Results: After systematic review, 3 eligible RCTs were selected that included 4,104 patients; 2,687 comprised the treatment group and 1,417 the control group. No significant increase in RR for seizures was registered with the new anti-androgens compared to placebo (RR 1.96; 95% confidence interval [CI] 0.40-9.61). However, 2 trials excluded patients with risk factors or a history of seizures. There was also no significant increase RR for grade >= 3 seizures (RR 2.50; 95% CI 0.12-52.02). RR for suffering dizziness (any grade) was 1.57 (95% CI 1.07-2.32) with the new anti-androgens, but no significant differences were found in the other study regarding neuropsychiatric events or grade >= 3 events. Conclusions: New anti-androgens (i.e., enzalutamide, apalutamide, and darolutamide) are acceptably safe in terms of seizures and neuropsychiatric toxicity compared to placebo in patients with nmCRPC.