Metabolic abnormalities were frequently documented during the first year after men with prostate cancer began concurrent androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), according to a large retrospective cohort study led by Amy L. Shaver, PhD, PharmD, MPH, and colleagues and published in JAMA Oncology.
Nearly 40% of patients had newly documented metabolic syndrome within 12 months, underscoring the need for early metabolic monitoring during treatment.
Metabolic syndrome includes a cluster of abnormalities such as obesity, insulin resistance, hypertension, and dyslipidemia. Although ADT is already known to increase metabolic risk, less is known about the timing and burden of metabolic dysfunction among patients receiving ADT together with newer ARPIs, which are increasingly used earlier in the course of prostate cancer treatment.
Study Details
The investigators conducted a retrospective cohort study using Epic Cosmos, a large deidentified electronic health record database. The analysis included adult men treated at U.S. institutions who had prostate cancer and received concurrent ADT and an ARPI between January 2014 and September 2025. ARPIs included abiraterone acetate, apalutamide, darolutamide, and enzalutamide.
Patients with documented metabolic syndrome, hypertension, obesity, insulin resistance, or dyslipidemia during the 6 months before treatment initiation were excluded. Because the study relied on electronic health records, however, the investigators cautioned that some chronic metabolic conditions may have been present but undocumented before treatment. For that reason, study outcomes represent newly documented metabolic abnormalities rather than definitively new-onset disease.
The primary endpoint was the incidence of metabolic syndrome during the 12 months after concurrent ADT-ARPI treatment began. Secondary endpoints included hypertension, obesity, dyslipidemia, and insulin resistance.
The cohort included 16,924 men with a mean age of 73.1 years. Thirty-five percent were younger than 70 years, 40% were aged 70 to 79 years, and 25% were aged 80 years or older. Medical ADT was used in 96.8% of patients, and enzalutamide was the most commonly used ARPI.
Key Findings
The cumulative incidence of metabolic syndrome increased steadily during the first year after ADT-ARPI initiation, reaching 39.1% at 12 months. Incidence differed by age, reaching 37.2% among men younger than 70 years, 41.7% among those aged 70 to 79 years, and 37.8% among those aged 80 years or older.
Hypertension was the most frequently documented metabolic abnormality, with a 12-month cumulative incidence of 83.0%. The corresponding incidences were 51.8% for dyslipidemia, 40.5% for obesity, and 24.0% for insulin resistance.
Metabolic abnormalities also appeared early. Among patients with a documented metabolic abnormality, the median time to first detection was 1.0 month. Median time to metabolic syndrome was 2.6 months, compared with 1.2 months for hypertension, 2.3 months for dyslipidemia, and 1.6 months for insulin resistance.
Age was associated with several metabolic outcomes. Compared with men younger than 70 years, those aged 70 to 79 years were more likely to develop insulin resistance, hypertension, dyslipidemia, and metabolic syndrome. The investigators also observed differences among individual ARPIs, but emphasized that these comparisons were exploratory and should not be interpreted as evidence for selecting one ARPI over another.
The study did not include an ADT-only comparison group. The investigators therefore could not determine how much of the observed metabolic burden was attributable specifically to ARPI therapy rather than ADT itself, aging, underlying cardiometabolic risk, or prostate cancer–related factors. Increased clinical surveillance after treatment initiation also may have contributed to detection of abnormalities that were already present.
The authors said the findings reinforce the importance of monitoring blood pressure, glucose, and lipid levels early during treatment and incorporating cardiometabolic risk management into prostate cancer care.
“Metabolic outcomes varied by age and treatment context, underscoring the importance of early and systematic metabolic monitoring,” they concluded. “Multidisciplinary strategies that incorporate cardiometabolic risk assessment and mitigation are needed to optimize long-term outcomes for men with prostate cancer.”
Amy L. Shaver, PhD, PharmD, MPH, and Grace Lu-Yao, PhD, of Sidney Kimmel Medical College and Sidney Kimmel Comprehensive Cancer Center at Jefferson, Philadelphia, are the corresponding authors of the article.
DISCLOSURE: The study was supported by resources at Sidney Kimmel Comprehensive Cancer Center at Jefferson and grants from the National Cancer Institute/National Institutes of Health. Dr. Zarrabi reported relationships with multiple pharmaceutical and health-care organizations; no other disclosures were reported. For full disclosures of the study authors, visit jamaoncology.com.
