The purpose of this study is to test a new medicine, vepugratinib, in comparison with placebo, to see if it is safe and can help people with a bladder cancer that is advanced or has spread.

Vepugratinib or placebo will be administered in combination with enfortumab vedotin and pembrolizumab.

Study participation could last up to approximately 6 years.

Inclusion Criteria:

• Have histologically confirmed, unresectable locally advanced or metastatic urothelial cancer (mUC). Individuals with mixed histology other than small cell or neuroendocrine carcinoma are eligible if a urothelial component is present.
• Have a qualifying fibroblast growth factor receptor 3 (FGFR3) genetic alteration determined via molecular testing from a tumor or blood sample obtained at or any time after diagnosis of advanced or metastatic urothelial cancer.
• Have measurable disease by investigator assessment defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Have adequate laboratory parameters

Exclusion Criteria:

• Have received prior systemic therapy for locally advanced or metastatic urothelial cancer (mUC).
• Have any unresolved toxicities greater than Grade 1 Common Terminology Criteria for Adverse Events ([CTCAE] version 5.0) from prior neoadjuvant or adjuvant systemic therapy.
• Have ongoing sensory or motor neuropathy of Grade 2 or higher
• Have untreated or uncontrolled central nervous system (CNS) involvement or any history of leptomeningeal disease.
• Current evidence corneal keratopathy or retinal disorder confirmed by ocular examination at screening.

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication or approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal should be approved by an independent review panel and researchers should sign a data sharing agreement.

There will be an open-label safety lead in.