Inclusion Criteria:
* Have histologically documented unresectable, locally advanced, or metastatic urothelial carcinoma.
* Measurable disease according to the New Response Evaluation Criteria in Solid Tumors (RECIST v1.1)38
a. 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.
* 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 available for tumor-informed ctDNA analysis.
* Meets Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.
* Adequate hematologic and organ function (Hb ≥ 8.0 g/dL; ANC ≥ 1.5x109 cells/L; CrCl \~30 mL/min; total bilirubin ≤ 1.5 mg/dL; ALT and AST within normal limits).
Exclusion Criteria:
* Previously received enfortumab, vedotin, or other monomethyl auristatin E (MMAE)-based ADCs.
* Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor within 12 months.
* Has received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed within 28 days prior to cycle 1 day 1.
* Has uncontrolled diabetes or ≥ grade III peripheral neuropathy.
* Patient's estimated life expectancy is less than 12 weeks.
* Has untreated central nervous system metastases.
* Experiences ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline.
* Is currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal). Routine antimicrobial prophylaxis is permitted.
* Has known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection.
* Has history of another invasive malignancy requiring treatment within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy (excluding localized prostate cancer or basal cell carcinoma of skin or squamous cell carcinoma of the skin).
* Has 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.
* Received radiotherapy within 2 weeks.
* Received major surgery (defined as requiring general anesthesia and \>24-hour inpatient hospitalization) within 2 weeks.
* Known severe (≥ Grade 3) hypersensitivity to any EV excipient contained in the drug formulation of EV.
* Has active keratitis or corneal ulcerations.
* Has a history of autoimmune disease that has required systemic immunosupressive treatment in the past 2 years, or uncontrolled autoimmune disease.
* 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 or ICPIs therapy following cystectomy with recurrence \>12 months from completion of therapy are permitted.
* Has a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
* Has received prior allogeneic stem cell or solid organ transplant.
* Received a live attenuated vaccine within 30 days.
