Survival Outcomes by Frailty and Comorbidities in Veterans Treated With Abiraterone and Enzalutamide for Metastatic Castration‐Resistant Prostate Cancer

ABSTRACT Background Androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide are common therapies in the management of metastatic castration‐resistant prostate cancer (mCRPC). However, the comparative effectiveness of these oral ARPIs in frail and comorbid patient populations remains uncertain. This study aims to determine whether one ARPI is associated with longer overall survival (OS) than the other, expanding upon prior work through inclusion of a contemporary patient cohort and examination of how comorbidities influence OS. Methods Using data from the nationwide Veterans Affairs (VA) healthcare system, we identified 8859 veterans with mCRPC treated with either abiraterone or enzalutamide between September 2014 and September 2022. Patients with prior docetaxel exposure were excluded, and frailty was defined using the VA Frailty Index (VA‐FI). Analyses were weighted for clinical covariates, including age, race, and BMI, using IPTW. Kaplan–Meier analysis was used to compare OS between treatment groups. Results Among frail patients with mCRPC, enzalutamide treatment was associated with longer OS compared to abiraterone (22.8 vs. 20.9 months, p = 0.001). Similarly, enzalutamide was associated with longer OS than abiraterone among patients with cardiovascular disease or diabetes (26.3 vs. 23.9 months, p = 0.023) and among patients without cardiovascular disease or diabetes (30.0 vs. 28.0 months, p = 0.019). Conclusions Enzalutamide was associated with improved OS compared to abiraterone in frail patients with mCRPC, regardless of comorbid cardiovascular disease or diabetes. These findings highlight the importance of considering specialized patient populations, including frailty and comorbidity profiles, in ARPI selection and clinical care. Trial Registration: NA