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This phase Ib trial evaluates the best dose, potential benefits, and/or side effects of erdafitinib in combination with enfortumab vedotin in treating patients with bladder cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and possesses genetic alterations in FGFR2/3 genes. Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals cancer cells to multiply. This may help keep cancer cells from growing and may kill them. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Giving erdafitinib in combination with enfortumab vedotin may shrink or stabilize metastatic bladder cancer with alterations in FGFR 2/3 genes.

PRIMARY OBJECTIVES: I. To determine the feasibility and safety of erdafitinib when combined with enfortumab vedotin (EV) for patients with metastatic urothelial carcinoma (mUC) harboring FGFR2/3 activating genomic alterations who are progressing following platinum-based chemotherapy and PD1/L1 inhibitors. II. To determine the maximally tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of EV when combined with erdafitinib. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To observe and record overall response rate (ORR). III. To observe and record duration of response (DOR). IV. To observe and record progression-free survival (PFS). V. To observe and record overall survival (OS). EXPLORATORY OBJECTIVES: I. Assess association of tumor PD-L1 and nectin-4 protein expression with response. II. Use commercial tissue next generation sequencing (NGS) assay to confirm FGFR status as well as to describe the genomic landscape of metastatic UC. III. Use commercial liquid NGS assay to assess genomic changes by circulating tumor (ct)-deoxyribonucleic acid (DNA) assessment to study mechanisms of resistance with treatment. IV. Assess pharmacokinetic (PK) of monomethyl auristatin E (MMAE) and erdafitinib. OUTLINE: This is a dose-escalation study of enfortumab vedotin in combination with fixed dose erdafitinib followed by a dose-expansion study of the drug combination. Patients receive erdafitinib orally (PO) once daily (QD) on days 1-28 of each cycle and enfortumab vedotin intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and blood sample collection throughout the trial and may undergo echocardiography or multigated acquisition (MUGA) scan during screening and bone scan throughout the study. After completion of study treatment, patients are followed up every 3 months for up to 2 years.