Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology

Inclusion Criteria: * Male or Female * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Metastatic disease or unresectable locally advanced disease * Histologically documented variant histology (nested, microcytic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (urachal and non-urachal). Variant histology tumors and non-urothelial tumors of ureter, urethra, urachus, or renal pelvis are included. Patients with mixed cell type are eligible if the predominant histology (over 50%) is variant or non-urothelial. All histological classifications will follow the 2016 WHO Classifications. * Untreated or having received any number of lines of prior therapy * Tumor tissue samples must be available for submission prior to initiation of study treatment. If not, agree to undergo biopsy * Patients must have measurable disease as defined by RECIST criteria 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter of \>= 10 mm for non-nodal lesions or short axis of \>= 15 mm for nodal lesions) on CT scan, MRI * Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator * The effects of study drugs on the developing human fetu…