Background: Cisplatin-based chemotherapy is the standard for first-line (1L) patients (pts) with locally advanced/metastatic urothelial cancer (LA/mUC). PD-1/PD-L1 inhibitors have promising durability of responses but 1L use is restricted to pts ineligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS ≥10) or pts ineligible for platinum-containing chemotherapy regardless of PD-L1 status. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with LA/mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. In the ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and antitumor activity of EV are investigated as monotherapy (mono) (for the first time in the 1L setting) and in combination with PD-1 inhibitor pembrolizumab (P) +/- chemotherapy in UC. An initial analysis of EV (1.25 mg/kg) + P (200 mg) (both drugs in investigational use here) in this study showed a 73.3% confirmed ORR in 45 1L cisplatin-ineligible LA/mUC pts (dose-escalation + expansion Cohort A) (Rosenberg ASCO 2020). Methods: A new Cohort K randomized 1:1 to 1.25 mg/kg EV mono or 1.25 mg/kg EV + 200 mg P provides additional information on EV + P and the contribution of activity from EV in cisplatin-ineligible pts with LA/mUC in the 1L setting. This cohort will enroll 150 adults (≥18 years) with LA/mUC and measurable disease per RECIST v1.1, and exclude pts with prior systemic treatment for LA/mUC, active CNS metastases, ongoing sensory or motor neuropathy (Grade ≥2), or uncontrolled diabetes. Cisplatin-ineligibility in this study is based on ≥1 of the following: ECOG of 2, creatinine clearance of ≥30 and < 60 mL/min, or hearing loss/dysfunction. In each 3-week cycle of this study, EV is administered on days 1 and 8, and P on day 1. The primary endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints include ORR per RECIST v1.1 by investigator assessment, DOR, DCR, PFS per RECIST v1.1 by BICR and investigator assessment, OS, safety, and tolerability. Sample size is not based on power calculation for formal hypothesis testing but is selected based on ORR estimate precision based on 95% CIs. Efficacy is summarized by treatment arm with no formal statistical comparisons between arms. The study opened in Oct 2017. Cohort K opened in Jan 2020. Clinical trial information: NCT03288545.