Risk-Enabled Therapy After Initiating EV/Pembro for Bladder Cancer

Inclusion Criteria:

* Primary urothelial or predominantly urothelial carcinoma of the bladder confirmed from pathology report. Patients with some component of variant histology mixed with predominant urothelial carcinoma will be allowed. Upper tract urothelial carcinoma patients are not allowed.
* Urothelial carcinoma of the prostatic urethra in men is allowed
* Histologic evidence of muscularis propria invasion.
* AJCC(22) clinical stage T2-T3 N0M0.
* No radiographic evidence of lymph node positive disease as per RECIST 1.1 (≥15 mm short axis diameter). If a lymph node is greater than 1.5 cm, it must be biopsy proven negative for the patient to be eligible.
* No metastatic disease (M0).
* ECOG performance status 0, or 1.
* Negative pregnancy test in women of child bearing potential within 72 hours of the first dose of study treatment.
* Normal organ and bone marrow function

Exclusion Criteria:

* Any component of small cell histology.
* Prior systemic chemotherapy for muscle-invasive urothelial cancer of the bladder.
* Uncontrolled diabetes (HbA1c \>8.5%)
* Pre-existing sensory or motor neuropathy grade \> 2
* Has a known additional malignancy that has had progression or has required active treatments in the last two years except for locally curable cancers that have been apparently cured. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Patients with intermediate or low risk prostate cancer as defined by the National Comprehensive Cancer Network (NCCN) risk stratification guidelines may be eligible for enrollment.
* Patients who have received experimental agents within 4 weeks of study entry.
* Patients who have received enfortumab vedotin based treatment in the past.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects of cytotoxic therapy.
* HIV-infected patients on effective anti-retroviral therapy with an undetectable viral load are eligible
* Any condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days prior to first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses \< 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease. Use of steroids as pre-medication for contrast allergy prior to PET scans or CT scans is permitted.
* History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Any history of autoimmune disease not explicitly listed above should be evaluated by the Principal Investigator and may result in exclusion based on clinical judgment.
* Prior treatment with CD137 agonists, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents. Has had an allogenic tissue/solid organ transplant.
* Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[IL\]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
* Allergy to EV, pembrolizumab or any excipient in the products