Major adverse cardiovascular events in androgen receptor signaling inhibitor–treated patients with metastatic castration-sensitive prostate cancer.

5107 Background: Cardiovascular disease is highly prevalent in the predominantly older male population with metastatic castration-sensitive prostate cancer (mCSPC). Androgen receptor pathway inhibitors (ARPIs) form the backbone of contemporary doublet and triplet treatment strategies, but—as with any systemic therapy—may influence patients’ underlying cardiovascular risk. This study compares the incidence of major adverse cardiovascular events (MACE) in real-world mCSPC patients treated with darolutamide versus abiraterone. Methods: This retrospective cohort study included patients in the nationwide VA healthcare system initiating doublet or triplet abiraterone or darolutamide for newly diagnosed mCSPC. After inverse probability of treatment weighting (IPTW), 1-year cumulative MACE incidence was estimated via Kaplan-Meier analysis. Doubly robust multivariable Cox regression using IPTW and multivariable competing risk regression with death as a competing risk assessed the association between treatment and MACE. All analyses were adjusted for age, race, prior MACE, NCI Charlson Score, smoking status, and prior hypertensive combination treatment. Results: Among 11,788 patients initiating darolutamide or abiraterone for mCSPC, 9,952 received abiraterone doublet, 936 received darolutamide doublet, 374 received abiraterone triplet, and 526 received darolutamide triplet therapy. In the weighted cohort, the 1-year cumulative incidence of MACE was lower in patients receiving darolutamide (7.2%, 95% confidence interval [CI] 5.6-9.0%) versus abiraterone (10.7%, CI 10.0-11.4%) doublet therapy. For triplet therapy, 1-year MACE incidence was 5.3% (CI 3.4-7.4%) with darolutamide and 9.6% (CI 5.9-13.6%) with abiraterone. In doubly robust multivariable Cox models, darolutamide doublet was associated with a lower hazard of MACE compared to abiraterone doublet (hazard ratio [HR] 0.78, CI 0.62-0.96, P=0.03). For triplet, patients receiving darolutamide had a HR of 0.73 for MACE (CI 0.39-1.31, p=0.29) compared to patients receiving abiraterone triplet therapy. Competing risk models showed consistent results. Conclusions: Darolutamide, particularly in doublet therapy, was associated with lower MACE risk than abiraterone. A similar point estimate in triplet therapy warrants validation in larger cohorts. These findings may inform treatment selection or prophylactic management to improve cardiovascular outcomes in mCSPC.