Risk of cardiovascular toxicities and hypertension in nonmetastatic castration-resistant prostate cancer patients treated with novel hormonal agents: a systematic review and meta-analysis

Background: With hormonal agents quickly expanding as novel therapeutic options in nonmetastatic castration-resistant prostate cancer (nmCRPC), the toxicity profile of enzalutamide, apalutamide, and darolutamide should be kept in mind. Methods: We performed an updated meta-analysis with the aim to analyze the risk of treatment-related cardiovascular (CV) events, any grade, and grade 3-4 (G3-4) hypertension in nmCRPC patients treated with enzalutamide, apalutamide, and darolutamide plus androgen deprivation therapy (ADT) versus ADT plus placebo in randomized controlled trials (RCTs). Results were compared by calculating Relative Risk (RR) with 95% confidence intervals (CIs); RRs were combined with Mantel-Haenszel method. Results: Three RCTs involving 4110 patients were available for the meta-analysis. According to our results, the addition of novel hormonal agents was associated with a significantly increased risk of CV events (RR = 1.71; 95% CI 1.29-2.27) and G3-4 hypertension (RR = 1.53; 95% CI 1.19-1.97). In addition, a trend toward a higher risk of any grade hypertension was reported in the experimental arm. Conclusions: The use of enzalutamide, apalutamide, and darolutamide in nmCRPC patients implies a careful benefit-risk assessment. Real-world, large-cohort studies are warranted to confirm the findings of our meta-analysis.