Impact of adding immunotherapy to chemotherapy for metastatic neuroendocrine bladder cancer in the National Cancer Database.

748 Background: Metastatic neuroendocrine bladder cancer is a rare and aggressive malignancy characterized by poor prognosis and limited effective treatment options. Standard chemotherapy has shown limited success, necessitating novel therapies. We hypothesized that adding immunotherapy to chemotherapy would improve overall survival (OS) in these patients. Methods: We conducted a retrospective cohort study of 1,410 patients diagnosed with metastatic neuroendocrine bladder cancer between 2004 and 2020 using the National Cancer Database (NCDB). Treatment groups included no treatment, chemotherapy alone, and combined immunochemotherapy. Survival outcomes were analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards regression models, adjusting for age, tumor size, Charlson-Deyo comorbidity score, and residential area. Results: Median OS was 1.8 months (95% CI: 1.6-2.0) for patients receiving no treatment (n=460), 9.6 months (95% CI: 8.9-10.1) for chemotherapy alone (n=860), and 11.7 months (95% CI: 9.6-14.8) for combined immunochemotherapy (n=90) (P < 0.001 for immunochemotherapy vs. both other groups). Further analysis revealed that first-line immunotherapy initiated within 30 days of chemotherapy (n=21) significantly improved OS (median 11.6 months; 95% CI: 6.8–16.1; P=0.0374) compared to chemotherapy alone. Notably, immunotherapy initiated after 30 days (n=69, median OS 12.4 months; 95% CI: 9.0–14.8; P=0.0264), whether as first-line or second-line therapy, also showed superior efficacy to chemotherapy alone. These findings suggest that if first-line immunotherapy is not administered, subsequent immunotherapy should still be considered. Multivariable Cox regression analysis showed that immunochemotherapy compared to chemotherapy alone was associated with a lower hazard for death (HR = 0.80; 95% CI: 0.66-0.97; P = 0.0242), while patients receiving no treatment had an increased risk of death (HR = 3.50; 95% CI: 3.00-3.90; P < 0.0001). Additional factors associated with increased mortality included older age, larger tumor size, and higher Charlson-Deyo score. Conclusions: Adding immunotherapy to chemotherapy significantly improved OS in metastatic neuroendocrine bladder cancer. First-line immunochemotherapy showed substantial benefits, but late initiation also improved outcomes. These findings support incorporating immunotherapy into first-line protocols and consider it for subsequent lines. Prospective clinical trials are needed to optimize immunotherapeutic strategies for this aggressive malignancy.