Study of Datopotamab Deruxtecan Plus Carboplatin or Cisplatin Versus Gemcitabine Plus Carboplatin or Cisplatin in Participants With Locally Advanced or Metastatic Urothelial Carcinoma

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.
• •a. 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:
• •1. QTcF interval \>450 ms based on the average of triplicate 12-lead (ECG per local read) at Screening.
• •2. Myocardial infarction within 6 months prior to randomization.
• •3. Uncontrolled angina pectoris within 6 months prior to randomization.
• •4. NYHA Class 3 or 4 congestive heart failure at Screening (See Section 10.3.2).
• •5. 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):
• •1. Anticancer therapy-induced neuropathy
• •2. 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)