Association of cardiovascular outcomes with GnRH agonist and antagonist therapy in non-metastatic prostate cancer.

5123 Background: Androgen deprivation therapy (ADT) is known to increase cardiometabolic risk. Randomized trials suggest GnRH antagonists may reduce major adverse cardiovascular events (MACE) compared with agonists, though studies were limited by short follow-up and low event rates. We evaluated the association between ADT mechanism and cardiovascular (CV) outcomes using large-scale real-world data. Methods: We conducted a retrospective cohort study using TriNetX database. Adult men with non-metastatic prostate cancer initiating ADT within 1 year of diagnosis were categorized by GnRH agonist or antagonist exposure. Cohorts were balanced using propensity score, matching demographics, CV co-morbidities, CV medications, and socioeconomic risk. Analyses were performed in the overall cohort and stratified by baseline CVD status. CV outcomes were assessed in years 1-10 following ADT initiation. The primary endpoint was MACE, defined as myocardial infarction, heart failure exacerbation, stroke or cardiac death. Secondary outcomes included atrial fibrillation/flutter, thromboembolism, mortality, and healthcare utilization. Results: After matching, 2,538 patients were included in both the GnRH antagonist and agonist group, including 785 with prior CVD and 1,460 without. In the overall cohort, GnRH antagonist therapy was associated with lower risk of MACE compared with GnRH agonists (OR 0.80, 95% CI 0.70–0.99; p=0.05) with an absolute risk of 8.0% vs 9.6%. Among patients with established CVD, antagonist use was associated with reduced MACE risk (OR 0.77, 95% CI 0.64–0.93; p<0.01) with an absolute risk of 19.6% vs 25.5%. In patients without prior CVD, antagonist use was associated with markedly lower MACE risk (OR 0.30, 95% CI 0.19–0.52; p<0.01) with an absolute risk of 1.3% vs 4.2%. For secondary outcomes, antagonist therapy was associated with lower risk of arterial thromboembolism and Emergency visits in the overall cohort, with no significant differences in all other outcomes. Among patients with baseline CVD, antagonist use was associated with lower risk of atrial fibrillation with no significant differences in all other outcomes. Among patients without baseline CVD, antagonist therapy was associated with lower risk of atrial fibrillation, healthcare utilization, and incident type 2 diabetes with no significant difference in all other outcomes. Conclusions: GnRH antagonist therapy was associated with lower rates of major adverse cardiovascular events compared with GnRH agonists, regardless of baseline cardiovascular disease status in years 1 through 10 after ADT initiation. Events occurring after the first year are more likely to reflect cumulative treatment-related cardiovascular toxicity, rather than unmasking baseline disease. These findings support further prospective, randomized trials to define the comparative CV safety of different ADT formulations.