Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality. New-generation androgen receptor pathway inhibitors (ARPIs), including enzalutamide and abiraterone, have improved survival but raise concerns about cardiovascular toxicity, particularly in an aging population with preexisting cardiovascular disease (CVD). While trials suggest similar efficacy between these agents, real-world data on their cardiovascular risks remain limited. This study aimed to compare the risks of major adverse cardiovascular events (MACE) and composite cardiovascular events in PCa patients receiving androgen deprivation therapy (ADT) with enzalutamide or abiraterone.

This retrospective cohort study utilized the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 2,013 PCa patients diagnosed between 2016 and 2020 who received ADT with enzalutamide or abiraterone were included. MACE was defined as ischemic heart disease, stroke, congestive heart failure, or all-cause mortality, while composite cardiovascular events included ischemic heart disease, stroke, congestive heart failure, or cardiovascular mortality. Kaplan-Meier survival analysis and hazard ratios (HRs) were used to compare cardiovascular risks between treatment groups, with subgroup analyses based on preexisting CVD.

Enzalutamide was associated with improved overall survival compared to Abiraterone (aHR: 0.83, 95% CI: 0.71–0.96, p=0.0147). When stratified by preexisting cardiovascular disease (CVD), Enzalutamide was associated with a lower but not statistically significant survival benefit in patients with preexisting CVD (aHR: 0.59, 95% CI: 0.32–1.06, p=0.0782), while the survival benefit remained significant in patients without preexisting CVD (aHR: 0.85, 95% CI: 0.73–0.99, p=0.0490). Cardiovascular-related mortality was lower in the low-risk subgroup for Enzalutamide compared to Abiraterone (0.95% vs. 1.42%), while non-cardiovascular mortality was also lower in both the low-risk (28.77% vs. 35.7%) and high-risk (23.44% vs. 44.05%) subgroups. Enzalutamide significantly reduced the risk of MACE compared to Abiraterone in patients with preexisting CVD (aHR: 0.61, 95% CI: 0.38–0.99, p=0.0448) and in those without preexisting CVD (aHR: 0.86, 95% CI: 0.74–0.99, p=0.0409), though the effect was more pronounced in high-risk patients. However, no significant difference was observed in composite cardiovascular events between Enzalutamide and Abiraterone in the overall population (aHR: 0.87, 95% CI: 0.68–1.12, p=0.2743) or in subgroups stratified by preexisting CVD. Kaplan-Meier analysis confirmed a greater cardiovascular benefit of Enzalutamide, particularly in high-risk patients, while composite cardiovascular event risk remained similar across all subgroups.

This real-world study suggests that enzalutamide is associated with a lower MACE risk and improved survival compared to abiraterone, particularly in patients with preexisting CVD. However, composite cardiovascular event risks were similar between the two regimens. These findings highlight the importance of cardiovascular risk assessment in treatment selection for PCa patients receiving APRIs. The study's findings have significant implications for guiding clinical decision-making, particularly in managing patients with preexisting cardiovascular conditions or those at high risk of cardiovascular events.