Enfortumab Vedotin + Pembrolizumab Induction to Spare the Bladder in MIBC

Inclusion Criteria: 1. Participants who are at least 18 years of age on the day of signing informed consent. 2. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 3. Patients with histologically confirmed cT2-4aN0-1M0 urothelial bladder cancer, seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery. Variant histology allowed, exceptions: * no pure (\>90%) squamous * no \>50% adenocarcinoma * no \>50% sarcomatoid component * no \>10% plasmacytoid component * no small cell component 4. Archival tumor tissue sample or newly obtained TURB of the bladder tumor is available. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 6. Have adequate organ function as defined in Table 3 below. Specimens must be collected within 14 days prior to the start of study intervention. 7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Not of childbearing potential (see section 9.2.1) OR * Of childbearing potential and: * Uses a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 120 days (pembrolizumab) or 180 days (EV) after the last dose of study intervention and agrees not to donate ova to others or freeze/store for her own use for the purpose of reproduction before start of study treatment. More details on contraceptive guidance can be found in section 9.2.1. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. * Has a negative urine or serum pregnancy test within 72 hours before the first dose of study intervention. Female subjects with false positive results and documented verification of negative pregnancy status may be eligible in consultation with the sponsor. * Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention (for pembrolizumab) or 180 days (EV) after the last dose of study intervention. A male participant agrees to the following during the intervention period and for at least 180 days after the last dose of EV: Refrains from donating sperm plus either: * Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent * Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) Exclusion Criteria: 1. Previous pelvic irradiation 2. Upper tract urothelial cancer 3. Extensive carcinoma in situ (CIS) of the bladder 4. Bilateral hydronephrosis 5. Previous intravenous systemic therapy for bladder cancer, including chemotherapy, checkpoint inhibition or antibody-drug conjugate. 6. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 7. Contra-indication to one of the study treatment components 8. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 10. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ that have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible. 11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, EV and/or any of its excipients in drug formulations (including histidine, trehalose dihydrate, and polysorbate 20). 12. Has active autoimmune disease that has required systemic treatment in the past 2 years. Exceptions that can still be included: * Endocrine disease with replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) * Patients with vitiligo, psoriasis or other mild skin disease * Gout is not considered an auto-immune disease. Patients should not have had an episode of active arthritis within 30 days of start of therapy. 13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 14. Ongoing sensory or motor neuropathy Grade 2 or higher. 15. 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. 16. A history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c ≥8% or HbA1c 7% to \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 17. Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. Active infection requiring systemic therapy is excluded as well. 18. Known active Human Immunodeficiency Virus infection, or tuberculosis, or other active infection: HIV-positive patients are eligible if the following applies: * Receives antiretroviral therapy (ART), without changes in drugs or dose modification, for at least 4 weeks prior to treatment and continued while enrolled on study. * CD4+ T-cell count ≥350 cells/mm3 at the time of screening * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening * No AIDS defining opportunistic infection within the past 12 months, or a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease. * In patients with a known history of hepatitis B infection, Hepatitis B surface antigen should be negative at time of screening. Patients having chronic hepatitis B are not eligible. * Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization. 19. Has not adequately recovered from major surgery or has ongoing surgical complications. 20. Major pelvic surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for the disease under study. 21. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 23. Has had an allogenic tissue/solid organ transplant.