Association between metabolic syndrome and treatment outcomes in metastatic prostate cancer: A retrospective cohort analysis.

Abstract

95 Background: Metabolic syndrome (MetS) affects 25–27% of metastatic prostate cancer patients (mPCa) receiving androgen deprivation therapy (ADT) and may amplify treatment-related metabolic toxicity. The differential impact of MetS on diabetes versus cardiovascular outcomes remains undefined. We examined these endpoints to inform toxicity management in 17,936 real-world patients. Methods: Using TriNetX (2004–2024), we identified 17,936 metastatic prostate cancer (mPCa) patients receiving ADT monotherapy (n=7,261; MetS 25.4%) or ADT plus novel hormonal therapy (ADT+NHT, n=10,675; MetS 26.7%). MetS was defined as ICD-10 E88.810 or ≥3 components (hypertension, dyslipidemia, diabetes, obesity). After 1:1 propensity matching for age, BMI, and baseline PSA, we analyzed 3,686 ADT and 5,710 ADT+NHT patients. Outcomes: metabolic toxicity (myocardial infarction, stroke, incident or progressive diabetes), isolated diabetes progression, PSA progression (≥0.2 ng/mL), and skeletal-related events (pathologic fractures, spinal compression). Median follow-up: 32 months (ADT), 25 months (ADT+NHT). Results: Metabolic syndrome doubled metabolic toxicity rates in both cohorts: 54.4% vs 27.6% for ADT (HR 2.52, 95% CI 2.26–2.80, p<0.0001) and 53.9% vs 28.4% for ADT+NHT (HR 2.31, 95% CI 2.12–2.52, p<0.0001). Notably, diabetes events comprised 90% of metabolic toxicity in MetS patients versus 78% in controls. Despite a 5-fold higher baseline diabetes prevalence in MetS patients, this effect persisted throughout follow-up. Importantly, cardiovascular events showed no increase despite metabolic burden (ADT: 5.2% vs 6.1%; ADT+NHT: 5.3% vs 6.6%), directly contradicting expected cardiovascular amplification in this high-risk population. Isolated diabetes analysis confirmed even higher risk: 49.3% vs 21.5% for ADT (HR 2.83, p<0.0001) and 48.5% vs 21.8% for ADT+NHT (HR 2.66, p<0.0001). No significant associations were observed with PSA progression (41% vs 42% ADT, p=0.44; 49% vs 51% ADT+NHT, p=0.02) or skeletal events. Conclusions: Metabolic syndrome more than doubled diabetes risk without increasing cardiovascular events in mPCa patients receiving ADT, challenging established toxicity assumptions. With diabetes comprising 90% of metabolic toxicity, our findings demonstrate that MetS-related risk is predominantly glycemic rather than cardiovascular. These findings suggest the need for further research to optimize monitoring and management strategies in this high-risk population.