Inclusion Criteria:

          -  Have a histologically confirmed diagnosis of urothelial carcinoma (cT2-T4aN0M0 or
             T1-T4aN1M0) with predominant (≥50%) urothelial histology and programmed cell death
             ligand 1 (PD-L1) expression assessment to be confirmed by Blinded Independent Central
             Review (BICR) (central pathology and/or imaging).

          -  Clinically non-metastatic bladder cancer determined by imaging

          -  Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and
             agreement to undergo curative intent standard RC + PLND (including prostatectomy if
             applicable)

          -  Ineligible for treatment with cisplatin, as defined by meeting at least one of the
             following criteria:

               -  Impaired renal function with measured or calculated creatinine clearance (CrCl)
                  30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of
                  Renal Disease [MDRD] equations, or measured by 24-hour urine collection)

               -  Eastern Cooperative Oncology Group (ECOG) Performance Status 2

               -  Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric
                  hearing loss

               -  New York Heart Association (NYHA) Class III heart failure

          -  Transurethral resection (TUR) of a bladder tumor that is submitted for central
             pathology assessment and adequate to determine urothelial histology and PD-L1
             expression assessment.

          -  ECOG performance status of 0, 1, or 2

          -  Adequate organ function

          -  A male participant is eligible to participate if he agrees to use contraception and
             refrain from donating sperm during the intervention period and for at least 180 days
             after the last dose of enfortumab vedotin. If the male participants are receiving
             pembrolizumab only or undergoing surgery only, there are no contraception
             requirements.

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least 1 of the following conditions applies: Not a (woman of
             childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective
             contraceptive method or be abstinent from heterosexual intercourse (as their preferred
             and usual lifestyle) during the intervention period and for at least 120 days after
             the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab
             vedotin; whichever comes last. A female participant must agree not to donate eggs
             during this period as well.

          -  A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before
             the first dose of study intervention.

        Exclusion Criteria:

          -  Known additional non-urothelial malignancy that is progressing or has required active
             anticancer treatment ≤3 years of study randomization, with certain exceptions

          -  Has ≥ N2 or metastatic disease (M1) as identified by imaging

          -  Received any prior systemic treatment, chemoradiation, and/or radiation therapy for
             for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer
             (NMIBC)

          -  Received prior therapy with an anti-programmed cell death protein 1 (PD-1),
             anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2
             (PD-L2), or with an agent directed to another stimulatory or co-inhibitory T-cell
             receptor

          -  Received prior systemic anticancer therapy including investigational agents within 3
             years prior to randomization

          -  Received any prior radiotherapy to the bladder

          -  Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder
             cancer (NMIBC) or MIBC

          -  Received a live vaccine within 30 days prior to the first dose of study intervention

          -  Current participation in or participation in a study of an investigational agent or
             use of an investigational device within 4 weeks prior to the first dose of study
             intervention

          -  Ongoing sensory or motor neuropathy Grade 2 or higher

          -  Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior the first dose of study
             drug. Physiologic replacement doses of corticosteroids are permitted for participants
             with adrenal insufficiency.

          -  Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of
             their excipients

          -  Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained
             in the drug formulation of enfortumab vedotin

          -  Active keratitis or corneal ulcerations. Participants with superficial punctate
             keratitis are allowed if the disorder is being adequately treated in the opinion of
             the investigator.

          -  Active autoimmune disease that has required systemic therapy in past 2 years (i.e.,
             with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic therapy and is allowed.

          -  History of uncontrolled diabetes

          -  History of (noninfectious) pneumonitis that required steroids, or current pneumonitis.

          -  Active infection requiring systemic therapy

          -  Has had an allogenic tissue/solid organ transplant