∙ Cohorts A and B

• Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra

• Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of platinum-containing chemotherapy

• At least one measurable lesion by investigator assessment based on RECIST version 1.1.

• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

∙ Cohort C

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra

• No prior systemic therapy for LA/mUC

‣ Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy

• At least one measurable lesion by investigator assessment based on RECIST v1.1.

• Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation

• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, on the provided tumor tissue sample

• ECOG performance status of 0, 1, or 2

∙ Cohort D

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra

• Based on a participant's eligibility to receive treatment with standard of care therapies in Japan, participants must have received all of the following lines of therapy for LA/mUC:

‣ a. One prior line of platinum-containing chemotherapy.

⁃ b. Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-line maintenance therapy or as second line treatment.

⁃ c. Prior enfortumab vedotin therapy.

• At least one measurable lesion by investigator assessment based on RECIST v1.1.

• ECOG performance status of 0 or 1

∙ Cohort E

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra

• No prior systemic therapy for LA/mUC

‣ Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy.

• At least one measurable lesion by investigator assessment based on RECIST v1.1.

• Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation

• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample

• ECOG performance status of 0 or 1

∙ Cohort G

• Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra

• Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of therapy containing enfortumab vedotin as monotherapy or in combination with pembrolizumab

‣ The last administration of enfortumab vedotin must be 90 days from the start of study treatment. Intervening therapies are allowed between the final dose of enfortumab vedotin and the start of disitamab vedotin.

• At least one measurable lesion by investigator assessment based on RECIST version 1.1.

• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1