Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer

Inclusion Criteria: * Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma * Measurable disease by investigator assessment according to RECIST v1.1 * Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy * Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: * Participants that received neoadjuvant chemotherapy with recurrence \>12 months from completion of therapy are permitted * Participants that received adjuvant chemotherapy following cystectomy with recurrence \>12 months from completion of therapy are permitted * Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment * Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 * Adequate hematologic and organ function Exclusion Criteria: * Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs) * Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor * Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor * Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment * Uncontrolled diabetes * Estimated life expectancy of less than 12 weeks * Active central nervous system (CNS) metastases * Ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline * 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. * History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy * Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization * Receipt of radiotherapy within 2 weeks prior to randomization * 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 * 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