Key Inclusion Criteria:
- 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 or 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 as specified in the protocol.
- 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).
- Archival tissue collected after the most recent anticancer treatment and within 12 months before the informed consent date is preferred.
- 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, the decision to rechallenge the participant with platinum therapy will be at the discretion of the investigator. Participants only receive carboplatin if they are ineligible for cisplatin. Participants are cisplatin-ineligible if they meet any of the following criteria: a. 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)
For Phase 2 part:
- 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.
For Phase 3 Part:
- Participants with borderline renal function CrCl ≥40 mL/min to <60 mL/min who have no other cisplatin ineligibility criteria (items b, c, and d) may receive cisplatin using a split-dose regimen, administered as cisplatin 35 mg/m\^2 on Days 1 and 8 of each 21-day cycle, for a maximum of 4 to 6 cycles.
- In participants with CrCl ≥50 mL/min to <60 mL/min, full-dose cisplatin may also be administered at the investigator's discretion, based on the overall clinical assessment.
The dosing schedule and dose level for Dato-DXd or gemcitabine are not altered when combined with either split-dose or full-dose cisplatin.
For both Phase 2 and Phase 3:
b. NCI-CTCAE Grade ≥2 audiometric hearing loss c. NCI-CTCAE Grade ≥2 peripheral neuropathy d. NYHA Class III heart failure
• Must have experienced radiographic progression or relapse during or after 1L of EV (or other agents with a vedotin payload) and pembrolizumab (or other PD-1/PD-L1 inhibitors).
Participants who discontinued EV (or other agents with a vedotin payload) and pembrolizumab (or other PD-1/PD-L1 inhibitors) 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 pembrolizumab (or other 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.
Key Exclusion Criteria:
- Has had prior systemic therapy other than the combination of EV and pembrolizumab for la/mUC. The following participants may be considered eligible after approval by the Sponsor's Medical Monitor or Sponsor's designee.
- Participant who progressed during or after treatments with assets that include either anti-Nectin 4 or vedotin payload (MMAE or other microtubule inhibitors) combined with PD1/PD-L1 inhibitors in 1L la/mUC.
- Treatment with any of the following:
1. History of an allogeneic bone marrow or solid organ transplant.
2. Concomitant treatment with any prohibited medications in this protocol.
3. Prior TROP2 directed ADC therapy.
- Uncontrolled or significant cardiovascular disease, including:
QTcF interval >470 ms based on the average of triplicate 12-lead (ECG per local read) at screening.
1. Screening myocardial infarction within 6 months prior to randomization.
2. Uncontrolled angina pectoris within 6 months prior to randomization.
3. NYHA Class 3 or 4 congestive heart failure at screening.
4. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg within 28 days before randomization that is not resolved despite maximal medical therapy).
- Has a history of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
- Has clinically severe pulmonary compromise as judged by the investigator resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior complete pneumonectomy.
- Toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet improved to NCI-CTCAE version 5.0 Grade ≤1 or baseline. Note: Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to randomization and managed with standard of care treatment) which the investigator deems related to previous anticancer therapy, comprised of (including but not limited to):
a. Anticancer therapy-induced neuropathy b. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies which may include:
- Hypothyroidism/ hyperthyroidism
- Type I diabetes
- Hyperglycemia
- Adrenal insufficiency
- Adrenalitis c. Skin hypopigmentation (vitiligo)