An open-label study to investigate the efficacy and safety of Dato-DXd + rilvegostomig vs SoC in adult participants with high-risk MIUC - TU-04

Inclusion Criteria

• Inclusion criteria:
• 1. Participant must be > 18 years of age at the time of signing the ICF.
• 2. Histologically confirmed MIUC of the bladder or upper tract.
• 3. Completed R0 radical resection 28 to 120 days before randomisation, with negative margins and no residual or metastatic disease.
• 4. Pathologic evidence of urothelial carcinoma at high-risk of recurrence and
• (a) not received neoadjuvant therapy and has pT3–pT4aN0, or any pT with pN+ stage
• (b) completed neoadjuvant treatment and has ypT2–ypT4a, or any ypT with ypN+ stage
• 5. No evidence of disease at screening,
• 6. ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation.
• 7. Minimum life expectancy of > 12 weeks at time of screening.
• 8. An archival surgical tumour sample must be available pre-randomisation for central testing.
• 9. Adequate organ and bone marrow function within 28 days before randomisation.
• Exclusion criteria:
• 1. Any tumour with predominant or pure high grade neuroendocrine carcinoma component.
• 2. Partial cystectomy in the setting of bladder cancer primary tumour or partial nephrectomy.
• 3. Any adjuvant systemic or radiation therapy post-surgery for urothelial carcinoma.
• 4. Severe or uncontrolled systemic diseases, history of organ transplant or allogeneic stem cell transplant, or psychological disorders/social situations, and/or substance abuse.
• 5. History of clinically significant corneal disease.
• 6. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention and of low potential risk for recurrence.
• 7. Ongoing toxicities except alopecia from prior cancer treatment must be Grade ≤ 1 or at baseline. Stable Grade 2 toxicities are allowed if unchanged for ≥3 months and managed by standard care.
• 8. Active or uncontrolled hepatitis B or C virus infection.
• 9. Known HIV infection that is not well controlled.
• 10. Any other active or uncontrolled infection including tuberculosis requiring systemic treatment that has not resolved by the time of randomisation.
• 11. 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.
• 12. Has clinically severe pulmonary function compromise.
• 13. Mean resting corrected QTcF > 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening
• 14. Uncontrolled or significant cardiac conditions.
• 15. Active or prior documented autoimmune or inflammatory disorders requiring systemic treatment in the past 5 years.
• 16. Prior exposure to TROP2-directed therapies, other ADCs with deruxtecan, therapeutic anti-cancer vaccines, anti-TIGIT therapy or any other anti-cancer therapy targeting immune-regulatory receptors or mechanisms.
• 17. Current or prior use of immunosuppressive medication within 14 days prior to treatment assignment/randomisation.
• 18. Known history of severe hypersensitivity reactions to any study drug
• 19. Not eligible to receive at least one of SoC according to local regulations/approvals.
• 20. Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.