KEYMAKER-U04 Substudy 04D: A Clinical Study of New Treatments Given With Enfortumab Vedotin and Pembrolizumab in People With Urothelial Cancer (MK-3475-04D/KEYMAKER-U04)

Researchers are looking for new ways to treat people with urothelial cancer (UC) that is locally advanced or metastatic. The standard treatment for locally advanced or metastatic UC is enfortumab vedotin (EV) given with pembrolizumab. The goals of this study are to learn about: * The safety of the study treatment when given with standard treatment and if people tolerate it * The number of people who have the cancer respond (cancer gets smaller or goes away) with the new study treatment when given with standard treatment.

Inclusion Criteria: The main inclusion criteria include but are not limited to the following: * Has histologically documented urothelial carcinoma (UC) that is locally advanced and unresectable or metastatic * Must provide a newly obtained or archival tumor tissue sample (core or excisional biopsy) * Must not have received prior systemic therapy for locally advanced or metastatic UC * If infected with Human Immunodeficiency Virus (HIV), has well controlled HIV on antiretroviral therapy * If positive for hepatitis B surface antigen, has received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load before randomization * If participant has a history of hepatitis C virus (HCV), has undetectable HCV viral load before randomization Exclusion Criteria: The main exclusion criteria include but are not limited to the following: * Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing * Has active keratitis or corneal ulcerations * Has active inflammatory bowel disease requiring immunosuppressive medication, or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea) * Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within the 6 months preceding study intervention * Has a history of uncontrolled diabetes * Has pleural effusion, ascites, and/or pericardial effusion that are symptomatic or require repeated drainage * Has active autoimmune disease that has required systemic treatment in the past 2 years * Has known additional malignancy that is progressing or has required active treatment within the past 2 years * Has known active central nervous system metastases and/or carcinomatous meningitis * Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease * Has an active infection requiring systemic therapy * If infected with HIV, has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease * Has concurrent active HBV and HCV infection * Has a history of stem cell/solid organ transplant