• Adult ≥18 years at the time the ICF is signed (if the legal age of consent is \> 18 years old, then follow the local regulatory requirements).

• Histologically or cytologically confirmed unresectable locally advanced (T4b, any N; or any T, N 2-3) or metastatic (any T, any N, M1) urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra.

• Participants with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible if the histology is predominantly urothelial.

• Note 1: Urachal, small cell, and adenocarcinoma histology is not permitted.

• Note 2: Participants with la/mUC and a history of nonclinically active prostate cancer are allowed into the trial if:

‣ Participant does not have radiological metastasis of a proven prostate cancer.

⁃ Participant with nonmetastatic prostate cancer do not have rising PSA (as determined using local testing by a validated or approved test method) defined as follows:

‣ • Increase in PSA within 2 consecutive measurements separated by at least 1 week (completed within 4 weeks prior to consent or within Screening) and neither of the measurements with an absolute value above 2 ng/mL.

⁃ Participant does not currently receive androgen deprivation therapy for the treatment of prostate cancer. • Must provide tumor tissue sample from archival tissue or newly obtained pretreatment biopsy for exploratory biomarker testing. Tumor tissue sample should not be collected from a lesion that was irradiated unless documentation can be provided confirming that the tumor tissue was collected at least 3 months after radiation and the lesion increased/appeared since radiation occurred. Tumor tissue must be of sufficient quantity (as defined in the laboratory manual).

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‣ Archival tissue collected after the most recent anticancer treatment and within 12 months before the informed consent date is preferred. • Participant must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment. Participants eligible for cisplatin will receive cisplatin. If a participant received gemcitabine, carboplatin or cisplatin for early UC in the adjuvant/neoadjuvant setting, ≥1 year must have passed since the last dose of these chemotherapy prior to the first dose of trial intervention. Participants only receive carboplatin if they are ineligible for cisplatin. Participants are cisplatin-ineligible if they meet any of the following criteria:

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‣ GFR \<60 mL/min (GFR may be estimated by calculated CrCl using the Cockcroft-Gault formula, Modification of Diet in Renal Disease, or 24-hour urine)

∙ Participants with a GFR \<60 mL/min but ≥50 mL/min but have no other cisplatin ineligibility criteria (items b, c, and d) may be considered cisplatin-eligible based on the investigator's clinical judgment.

⁃ NCI-CTCAE Grade ≥2 audiometric hearing loss

⁃ NCI-CTCAE Grade ≥2 peripheral neuropathy

⁃ NYHA Class III heart failure • Must have experienced radiographic progression or relapse during or after 1L of EV and pembrolizumab.

• Participant who discontinued EV and pembrolizumab in 1L due to toxicity are eligible if they have experienced disease progression following discontinuation. Participant who received EV (or other agents with a vedotin payload) plus PD 1/PD-L1 inhibitors in a neoadjuvant/adjuvant setting and progressed during treatment or within 12 months of treatment completion will also be considered for enrollment, after approval by the Sponsor's Medical Monitor or Sponsor's designee.