Neoadjuvant Enfortumab Vedotin Plus Pembrolizumab in Muscle-Invasive Bladder Cancer and Upper Tract Urothelial Carcinoma

Inclusion Criteria:

* Adults ≥ 18 years of age.
* ECOG Performance Status of 0-2
* For Cohort A, a clinical or pathological diagnosis consistent with muscle-invasive urothelial carcinoma of the bladder (locoregional), with a clinical staging of T2 or higher, N0 to N2, and M0.

For Cohort B, a clinical or pathological diagnosis of upper tract urothelial carcinoma, with high-intermediate risk or higher per NCCN guidelines, planned for definitive surgery.

* High-intermediate: High grade + Unifocal \<1.5 cm
* High: High grade + Multifocal or \>1.5 cm or high-grade renal obstruction or invasion on axial imaging Any proportion of divergent differentiation is permitted across all histologies (except neuroendocrine - see exclusion criteria), as long as a urothelial component is identified.

  * Eligible to receive enfortumab vedotin plus pembrolizumab (EV-P) in the opinion of the investigators.
  * Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
  * Subjects must not have more than one active malignancy at the time of enrollment.

Note: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen or primary endpoint (as determined by the treating physician) are eligible for this trial.

\- Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of EV-P to minimize the risk of pregnancy. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.

SOCBP includes any subject who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

* Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
* For subjects with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

  * Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 4 months following the last dose of EV-P.

Exclusion Criteria:

* Histology that contains any component of neuroendocrine carcinoma.
* Any known contraindications to enfortumab vedotin plus pembrolizumab.
* Subjects who are confirmed to be pregnant or breastfeeding.
* History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
* Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose.
* Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.