Association of GLP-1 receptor agonist therapy with BCG response in high-risk non–muscle invasive bladder cancer.

4620 Background: Observational studies suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced cancer incidence and improved survival in patients with established malignancies. Cohort data in lung cancer also suggest improved outcomes with immune checkpoint inhibitor therapy among patients receiving GLP-1RAs, raising the possibility of enhanced anti-tumor immunity. Intravesical Bacillus Calmette–Guérin (BCG) remains the mainstay treatment for high-risk (HR) non-muscle invasive bladder cancer (NMIBC). We hypothesized that GLP-1RA exposure during BCG therapy is associated with more favorable clinical outcomes in HR-NMIBC. Methods: Patients with HR- NMIBC treated between November 1 st 2015 to November 1 st 2025 were evaluated retrospectively using the TriNetX US Research Network. Patients were stratified by GLP-1RA exposure before BCG initiation (with or without overlap during BCG) versus no exposure. Cohorts were propensity score–matched for demographics and comorbidities, and outcomes were evaluated using multivariable logistic regression. The primary outcome was mortality; secondary outcomes included recurrence, progression to muscle-invasive bladder cancer (MIBC), cystectomy, and distant metastasis. Results: A total of 12,423 patients were evaluated, of which 791 (7%) received GLP-1RAs, while 11,630 (93%) did not. After propensity score matching, 787 patients were analyzed in each group. The average age in both cohorts was 73 years. Majority of patients were white (85%), male (80%), and non-Hispanic (85%). The distribution of GLP-1RAs use included semaglutide (67%), dulaglutide (37%), tirzepatide (21%), liraglutide (17%), exenatide (8%), and lixisenatide (1%). Patients who received GLP-1RAs demonstrated a significant reduction in 10-year mortality (RR 0.65; 95% CI 0.45 – 0.93, p = 0.017) and a lower risk of developing MIBC (RR 0.43; 95% CI 0.26 – 0.89; p = 0.018). No significant changes were noted in the risk of disease recurrence, radical cystectomy or distant metastasis (Table 1). Conclusions: In this real-world, retrospective, multi-cohort analysis we found that patients who received GLP-1RAs prior to BCG treatment are at a decreased risk of all-cause mortality, and less likely to develop progression to MIBC. This study underscores the need for further evaluation of GLP-1RAs in patients with NMIBC treated with BCG. Outcomes comparing HR-NMIBC patients exposed to GLP-1RA prior to BCG therapy versus those without exposure. Outcome Risk Ratio (95% CI) p- value Mortality 0.65 (0.45 – 0.93) 0.017 MIBC progression 0.43 (0.26 – 0.89) 0.018 NMIBC recurrence 0.98 (0.89 – 1.09) 0.84 Radical cystectomy 0.94 (0.72 – 1.22) 0.65 Distant metastasis 0.83 (0.62 – 1.11) 0.19