A Study of Efficacy and Safety of Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)

Inclusion Criteria:

* Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).

  * Participants with mixed histology are eligible provided the urothelial component is ≥50% (and \<10% plasmacytoid component)
  * Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally)
* Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:

  * Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
  * Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence \>12 months from completion of therapy are permitted.
* Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
* Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with \<Grade 2 neuropathy are eligible.

Exclusion Criteria:

* Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
* Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
* Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
* Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
* Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
* Has a history of uncontrolled diabetes.
* Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
* Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.
* Has a known history of human immunodeficiency virus (HIV) infection.
* Has hepatitis B or hepatitis C virus infection.
* Has had major surgery within 4 weeks prior to first dose of study intervention.
* Has had an allogenic tissue/solid organ transplant