Non-fatal major cardiovascular events associated with androgen receptor pathway inhibitors in prostate cancer: systematic review and network meta-analysis

Importance Major cardiovascular events (MACE) cause substantial morbidity and mortality in patients with prostate cancer (PC). Androgen receptor pathway inhibitors (ARPIs) are associated with cardiovascular toxicity, yet comparative data on the risk of MACE are lacking. Objective To evaluate the risk of non-fatal MACE among abiraterone, apalutamide, darolutamide, and enzalutamide users, in patients with localized or metastatic PC. Methods We conducted a Systematic search of Medline, Cochrane, and ClinicalTrials.gov through June 2025. Randomized controlled trials (RCTs) reporting cardiovascular events with ARPI monotherapy or combination therapy were eligible. Data on study design, patient characteristics and cardiovascular events were extracted. Network meta-analysis (NMA) was conducted using frequentist and Bayesian approaches, with surface under the cumulative ranking curve (SUCRA) for ARPI comparisons. The primary endpoint was the risk of non-fatal MACE (myocardial infarction, ischemic stroke or heart failure). Secondary outcomes were myocardial infarction, ischemic stroke, heart failure, and other cardiovascular events. Results Thirty-nine trials including 22,717 patients were analyzed. SUCRA rankings showed that apalutamide and enzalutamide had the highest probability of non-fatal MACE (0.18 and 0.23 respectively, with lower ranks indicating higher probability), whereas control arms and darolutamide had the lowest (0.93 and 0.59 respectively). Apalutamide (OR 2.53, 95% CI [1.22;5.26]), enzalutamide (OR 2.30, 95% CI [1.61;3.28]), and abiraterone (OR 2.06, 95% CI [1.29;3.28]) but not darolutamide (OR 1.39, 95% CI [0.77;2.51]) were associated with a significantly higher risk of non-fatal MACE compared with control. Heterogeneity was low (I² = 25.1%) and no network inconsistency was detected (p = 0.665). Conclusion And Relevance Apalutamide and enzalutamide carry higher risk of non-fatal MACE, whereas darolutamide shows the lowest risk, supporting its preferential use in patients with elevated cardiovascular risk.