Inclusion Criteria:
* Participant aged ≥ 18 years.
* Disease criteria:
* Histologically confirmed muscle-invasive urothelial carcinoma (T2-T3N0M0) without small cell variant histology of bladder. Other variant histologies are allowed if urothelial histology is present.
* No evidence of local or distant metastasis on CT scans.
* Urothelial carcinomas not originating from the bladder (eg, upper tract \[ureters, renal pelvis\], urethra) are not eligible.
* Eligible to receive enfortumab vedotin and pembrolizumab.
* ECOG Performance Status ≤ 2.
* Adequate organ function as defined as:
* Hematologic:
* Absolute neutrophil count ≥ 1500/mm3
* Platelet count ≥ 100,000/mm3
* Hemoglobin ≥ 10 g/dL
* Hepatic:
* Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN), ≤3× ULN for subjects with suspected Gilbert's syndrome with direct bilirubin ≤ ULN.
----AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
* Renal:
* Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula (or measured by 24-hour urine collection).
* Participants must adhere to the following sex and contraceptive/barrier requirements:
* If participant is of childbearing potential, they must have a negative pregnancy test.
* For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause or having undergone surgical sterilization (bilateral oophorectomy or hysterectomy). The following age-specific requirements apply:
* \< 50 years of age:
* Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
--≥ 50 years of age:
* Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
* Had radiation-induced menopause with last menses \>1 year ago; or
* Had chemotherapy-induced menopause with last menses \>1 year ago
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
* Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.2 and 5.4.3.
* Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have resolved or have been determined to be clinically stable per the Investigator.
* Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
* Participant has been counseled on standard of care treatment options available to them and has expressed they are interested in pursuing bladder preservation without cystectomy or radiation.
The discussion regarding the choice of standard therapy offered, if available, and patient's choice to decline standard therapy should be documented clearly in the research chart.
Exclusion Criteria:
* Prior systemic therapy for urothelial cancer.
* Receiving other systemic investigational agents for urothelial cancer.
* Hemoglobin A1c \> 8% or 7-8% with associated diabetes symptoms.
* Autoimmune disease requiring systemic steroids or immunosuppressive agents in the last 2 years.
* Neuropathy Grade ≥2.
* Prior radiotherapy for urothelial cancer.
* Major surgery within 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery per clinical investigator.
* The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact study objectives or the participant's safety or ability to participate in the study.
* Known metastatic disease.
* Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
* Cardiovascular disorders:
* Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias per clinical investigator.
* Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other significant ischemic events per clinical investigator, within 3 months before the first dose. Subjects with pulmonary embolism or deep vein thrombosis if adequately managed can be enrolled.
* Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)
* Active infection expected to interfere with study treatment in the opinion of the investigator.
* Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.
--Note: Participants on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.
* Hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.
Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
* Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v6.0 Grade ≥ 3).
* Participants taking prohibited medications as described in Section 6.8.2.
