Metabolic Dysfunction After Initiation of Androgen Receptor Pathway Inhibitors in Prostate Cancer

Importance Metabolic syndrome (MetS) includes obesity, insulin resistance, hypertension, and dyslipidemia. While androgen deprivation therapy (ADT) is associated with an increased risk of dyslipidemia, adiposity, and MetS, evidence is limited on the occurrence and timing of metabolic dysfunction among men receiving concurrent androgen receptor pathway inhibitor (ARPI) therapy and whether patterns vary by age. Objective To characterize the occurrence and rate of MetS during the first year following initiation of ADT-ARPI, examine associations with age and ARPI type, and evaluate component metabolic outcomes (secondary end points). Design, Setting, and Participants This retrospective cohort study of adult patients from January 2014 to September 2025 with up to 12 months of follow-up per person used data from a national, deidentified health record dataset (Epic Cosmos) and included patients with prostate cancer who initiated treatment with ADT-ARPI (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) without evidence of MetS or its components before treatment. Data were analyzed between October 2025 and January 2026 (further analyses were done with revisions through May 2026). Exposure Concurrent ADT and ARPI use, with index date defined as the first date of overlap between therapies. Main Outcomes and Measures New-onset MetS during the 12 months following the index date. Secondary outcomes included individual metabolic abnormalities. Results The cohort included 16 924 men with prostate cancer (mean [SD] age, 73.1 [9.1] y; 509 [3.0%] Asian individuals, 912 [5.4%] Hispanic individuals, 3562 [21.0%] non-Hispanic Black individuals, and 11 083 [65.5%] non-Hispanic White individuals). Medical ADT use predominated, and enzalutamide was the most frequently used ARPI. During the first year following initiation of concurrent ADT and ARPI therapy, the cumulative incidence of metabolic syndrome increased steadily, reaching nearly 40%, and varied by age group. Hypertension was the most frequently documented component outcome. Metabolic associations varied by age, with the highest incidence of metabolic syndrome among patients aged 70 to 79 years (51.7 events per 1000 person-months; 95% CI, 50.7-53.9). Heterogeneity in metabolic outcomes by ARPI type was observed in exploratory analyses. Conclusions and Relevance This study found that while ARPIs are standard of care for advanced prostate cancer, metabolic abnormalities were frequently documented shortly after initiation of concurrent ADT and ARPI therapy. This suggests that monitoring should extend beyond cancer-specific outcomes to include early detection of metabolic dysfunction, ideally through multidisciplinary care. The early burden of metabolic abnormalities highlights the need to evaluate scalable interventions addressing cardiometabolic risk in men with prostate cancer.