Enfortumab Vedotin in Combination With Pembrolizumab vs. Concurrent Chemoradiotherapy (cCRT) in People With Muscle Invasive Bladder Cancer (EV-309)

Inclusion Criteria: * Has histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology staged cT2-T4aN0M0 * Tissue comprising muscle-invasive urothelial cancer must be submitted for clinical staging at baseline * Eligible for and agree to receive chemoradiotherapy and one of the protocol-specified radiosensitizing chemotherapy regimens * Fit for systemic therapy and elect bladder preservation, including participants who are ineligible for or have elected not to undergo cystectomy * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Exclusion Criteria: * Advanced or metastatic disease (N+, M1), non-urothelial carcinoma, diffuse or multifocal CIS, urothelial carcinoma or histological variant at any site outside the urinary bladder within previous 24 months prior to randomization except Ta/T1/CIS of the upper urinary tract including renal pelvis and ureter if the participant had undergone complete nephrectomy * Has received any prior systemic treatment, chemoradiation, and/or radiation for MIBC or NMIBC * Prior pelvic radiation for any reason * Inadequate bladder function * Other active malignancies within 3 years prior to randomization * Previously treated with enfortumab vedotin or other MMAE-based antibody-drug conjugates (ADCs) * Previously treated with a PD(L)-1 inhibitor, defined as a PD-1 inhibitor or PD-L1 inhibitor * Uncontrolled diabetes * Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted * Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection * Received major surgery (defined as requiring general anesthesia and \>24 hour inpatient hospitalization) within 4 weeks prior to randomization * Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin * Known genetic disorders associated with radiosensitivity (eg, ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi syndrome) * Active keratitis or corneal ulcerations * History of autoimmune disease that has required systemic treatment in the past 2 years * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Prior allogeneic stem cell or solid organ transplant * Received a live attenuated vaccine within 30 days prior to randomization