Durvalumab, Tremelimumab, and Enfortumab Vedotin in Muscle-Invasive Bladder Cancer

BackgroundThe standard of care for patients with muscle-invasive bladder cancer continues to evolve. Whether perioperative durvalumab, with or without tremelimumab, plus neoadjuvant enfortumab vedotin is effective in such patients is unknown. MethodsIn this phase 3 open-label trial, we randomly assigned, in a 1:1:1 ratio, patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy to receive neoadjuvant durvalumab–enfortumab vedotin every 3 weeks for three cycles, followed by radical cystectomy and then adjuvant durvalumab every 4 weeks for nine cycles; neoadjuvant durvalumab–tremelimumab–enfortumab vedotin (tremelimumab for two cycles only), radical cystectomy, and adjuvant durvalumab–tremelimumab (tremelimumab for one cycle only); or radical cystectomy alone (control). The dual primary end points were event-free survival in each of the two durvalumab groups as compared with that in the control group. The two durvalumab groups were not compared with each other. The key secondary end point was overall survival. ResultsIn total, 233 patients were assigned to the durvalumab–enfortumab vedotin group, 233 to the durvalumab–tremelimumab–enfortumab vedotin group, and 229 to the control group. Estimated event-free survival at 24 months was 63.5% (95% confidence interval [CI], 56.5 to 69.7) with durvalumab–enfortumab vedotin and 45.1% (95% CI, 38.2 to 51.8) with control (hazard ratio for an event or death, 0.51; 95% CI, 0.38 to 0.67; P<0.001); estimated overall survival at 24 months was 78.4% and 69.4%, respectively (hazard ratio for death, 0.58; 95% CI, 0.40 to 0.83; P=0.003). Estimated event-free survival at 24 months was 60.1% (95% CI, 53.2 to 66.2) with durvalumab–tremelimumab–enfortumab vedotin (hazard ratio for an event or death vs. control, 0.61; 95% CI, 0.47 to 0.80; P<0.001). Grade 3 or higher adverse events occurred in 71.1% of patients in the durvalumab–enfortumab vedotin group (treatment-related, 30.7%), in 79.5% of those in the durvalumab–tremelimumab–enfortumab vedotin group (treatment-related, 44.5%), and in 50.2% of those in the control group. ConclusionsPerioperative durvalumab with or without tremelimumab plus three cycles of neoadjuvant enfortumab vedotin resulted in significantly better event-free survival outcomes than surgery alone. Perioperative durvalumab plus enfortumab vedotin led to significantly better overall survival outcomes than surgery alone. Grade 3 or higher adverse events of any cause were noted in more than half the patients in the durvalumab groups. (Funded by AstraZeneca; VOLGA ClinicalTrials.gov number, NCT04960709; EudraCT number, 2020-005452-38.)