Metabolic syndrome frequent during first year of ADT-ARPI therapy for prostate cancer

Metabolic syndrome was newly documented in nearly 40% of men with prostate cancer during the first year after initiation of concurrent androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), according to a large retrospective cohort study published in JAMA Oncology.¹

The analysis of 16,924 men without documented metabolic syndrome or its individual components before treatment found that the cumulative incidence of metabolic syndrome reached 39.1% at 12 months. Hypertension was the most frequently documented metabolic abnormality.

Study design and findings

Investigators used data from Epic Cosmos, a national, deidentified electronic health record database, to conduct a retrospective cohort study of adults with prostate cancer who initiated concurrent ADT and an ARPI between January 2014 and September 2025. The ARPIs included abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa). The index date was defined as the first date on which the 2 therapies (ADT+ARPI) overlapped.

Patients with documented metabolic syndrome and its component conditions (hypertension, obesity, insulin resistance, or dyslipidemia) during the 6-month period before the index date were excluded. The cohort had a mean age of 73.1 years; 21.0% of patients were non-Hispanic Black, 65.5% were non-Hispanic White, 5.4% were Hispanic, and 3.0% were Asian. Medical ADT was used in 96.8% of patients, and enzalutamide was the most frequently used ARPI (39.1%).

The primary outcome was metabolic syndrome during the 12 months after treatment initiation, with hypertension, obesity, dyslipidemia, and insulin resistance assessed as secondary outcomes.

The cumulative incidence of metabolic syndrome increased steadily throughout the first year, with a cumulative incidence of 39.1% (95% CI, 38.3 to 40.0) at 12 months. The incidence was highest among men aged 70 to 79 years, at 51.7 events per 1000 person-months (95% CI, 50.7 to 53.9).

Individual metabolic abnormalities were documented particularly frequently. Hypertension had a 12-month cumulative incidence of 83.0%, followed by dyslipidemia at 51.8%, obesity at 40.5%, and insulin resistance at 24.0%. The median time to first documented metabolic abnormality among affected patients was approximately 1 month (IQR, 0.3 to 2.9), while the median time to documentation of metabolic syndrome was 2.6 months (IQR, 1.1 to 5.5).

No statistically significant interaction was observed based on age and ARPI type, but associations were observed.

According to the authors, “Compared with patients younger than 70 years, those aged 70 to 79 years had higher hazards of insulin resistance (aHR, 1.26; 95% CI, 1.15-1.38), hypertension (aHR, 1.10; 95% CI, 1.04-1.15), dyslipidemia (aHR, 1.33; 95% CI, 1.25-1.41), and MetS (aHR, 1.09; 95% CI, 1.02-1.17), while obesity risk declined with advancing age.”

Further, when compared with abiraterone, enzalutamide and apalutamide were associated with lower hazards of hypertension ([HR, 0.85; 95% CI, 0.81 to 0.88] and [0.81; 95%, CI 0.76 to 0.85], respectively). Apalutamide also was also associated with a higher hazards of dyslipidemia (HR, 1.08; 95% CI, 1.00 to 1.16), insulin resistance (HR, 1.10; 95% CI, 0.99 to 1.23), and metabolic syndrome (HR 1.04; 95% CI, 0.96 to 1.14), and enzalutamide was associated with higher hazards of insulin resistance (HR, 1.08; 95% CI, 1.00 to 1.18).

Limitations and next steps

The principal limitation is the absence of an ADT-only comparator group. Consequently, the study estimates the burden and timing of metabolic abnormalities observed after ADT-ARPI initiation rather than the incremental risk associated with adding an ARPI.

Additional limitations include the retrospective nature of the analysis, reliance on EHR documentation, potential surveillance bias, possible loss to follow-up when patients received care outside Epic-affiliated systems, and use of body mass index as a proxy for adiposity. Disease setting, tumor burden, lifestyle factors and some concurrent anticancer therapies were not fully captured. ARPI-specific comparisons are particularly susceptible to confounding by indication.

Future prospective studies will be needed to determine whether cardiometabolic interventions can reduce clinically meaningful metabolic events without compromising oncologic outcomes. However, according to the authors, the current findings support early and systematic metabolic monitoring to improve long-term outcomes for men with prostate cancer.

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