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 urothelialcarcinoma (la/mUC).

• Participants with mixed histology are eligible provided the urothelialcomponent 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 inearlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) arepermitted:

• Participants that received neoadjuvant or adjuvant chemotherapy are permitted.

• Participants who received anti- programmed cell death 1 protein (PD-1) orprogrammed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence >12 months from completion oftherapy are permitted.

• Must provide an archival tumor tissue sample or newly obtained core or excisionalbiopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequatefor biomarker evaluation. A newly obtained biopsy is strongly preferred, but notrequired if archival tissue is evaluable.

• Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 orbaseline. 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 undergonepotentially curative therapy with no evidence of that disease recurrence for atleast 3 years since initiation of that therapy.

• Central nervous system (CNS) metastases are permitted on-study if all of thefollowing are true: a) CNS metastases have been clinically stable for at least 4weeks prior to screening and baseline scans show no evidence of new or enlargedmetastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone orequivalent for at least 2 weeks (if requiring steroid treatment); c) participantdoes not have leptomeningeal disease.

• Has received a live or live-attenuated vaccine within 30 days prior to the firstdose of study intervention.

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapyor any other form of immunosuppressive therapy within 7 days prior the first dose ofstudy intervention. Inhaled or topical steroids are permitted in the absence ofactive autoimmune disease. Physiologic replacement doses of corticosteroids arepermitted for participants with adrenal insufficiency.

• Has active keratitis or corneal ulcerations. Superficial punctate keratitis isallowed if the disorder is being adequately treated in the opinion of theinvestigator.

• Has an active autoimmune disease that has required systemic treatment in past 2years except replacement therapy.

• Has a history of uncontrolled diabetes.

• Has a history of (noninfectious) pneumonitis that required steroids or has currentpneumonitis

• 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