Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)

Inclusion Criteria:

• Have a histologically confirmed diagnosis of urothelial carcinoma/muscle-invasivebladder cancer [MIBC] (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelialhistology to be confirmed by Blinded Independent Central Review (BICR) (centralpathology and/or imaging).

• Clinically nonmetastatic bladder cancer determined by imaging

• Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), andagreement to undergo curative intent standard RC + PLND (including prostatectomy ifapplicable)

• Ineligible for treatment with cisplatin, as defined by meeting at least one of thefollowing criteria OR be eligible for treatment with cisplatin but decline treatmentwith cisplatin-based chemotherapy:

• Impaired renal function with measured or calculated creatinine clearance (CrCl) 30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet ofRenal 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 audiometrichearing loss

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

• Transurethral resection (TUR) of a bladder tumor that is submitted for centralpathology assessment and adequate to determine urothelial histology and PD-L1expression 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 andrefrain from donating sperm during the intervention period and for at least 180 daysafter the last dose of enfortumab vedotin. If the male participants are receivingpembrolizumab only or undergoing surgery only, there are no contraceptionrequirements

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

• A WOCBP must have a negative highly sensitive pregnancy test within 24 hours beforethe first dose of study intervention

Exclusion Criteria:

• Known additional nonurothelial malignancy that is progressing or has required activeanticancer 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 formuscle-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 coinhibitory T-cellreceptor

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

• Received any prior radiotherapy to the bladder

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

• Received a live or live-attenuated vaccine within 30 days before the first dose ofstudy intervention

• Current participation in or participation in a study of an investigational agent oruse of an investigational device within 4 weeks prior to the first dose of studyintervention

• Ongoing sensory or motor neuropathy Grade 2 or higher

• Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior the first dose of studydrug. Physiologic replacement doses of corticosteroids are permitted forparticipants with adrenal insufficiency.

• Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any oftheir excipients

• Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient containedin the drug formulation of enfortumab vedotin

• Active keratitis or corneal ulcerations. Participants with superficial punctatekeratitis are allowed if the disorder is being adequately treated in the opinion ofthe 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 corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered a formof systemic therapy and is allowed

• Has uncontrolled diabetes

• History of (noninfectious) pneumonitis that required steroids, or currentpneumonitis

• Active infection requiring systemic therapy

• Has had an allogeneic tissue/solid organ transplant