An Open-label Study to Investigate the Efficacy and Safety of Dato-DXd + Rilvegostomig vs SoC in Adult Participants With High-risk MIUC

Prior treatment

• Any adjuvant systemic or radiation therapy post-surgery for urothelial carcinoma.
• 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.
• Active or prior documented autoimmune or inflammatory disorders requiring systemic treatment in the past 5 years.
• 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.
• Current or prior use of immunosuppressive medication within 14 days prior to treatment assignment/randomisation.

Other illness

• Partial cystectomy in the setting of bladder cancer primary tumour or partial nephrectomy.
• Severe or uncontrolled systemic diseases, history of organ transplant or allogeneic stem cell transplant, or psychological disorders/social situations, and/or substance abuse.
• History of clinically significant corneal disease.
• 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.
• Active or uncontrolled hepatitis B or C virus infection.
• Known HIV infection that is not well controlled.
• Any other active or uncontrolled infection including tuberculosis requiring systemic treatment that has not resolved by the time of randomisation.
• 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.
• Uncontrolled or significant cardiac conditions.
• Known history of severe hypersensitivity reactions to any study drug

Other

• Any tumour with predominant or pure high grade neuroendocrine carcinoma component.
• Has clinically severe pulmonary function compromise.
• Mean resting corrected QTcF \> 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening
• Not eligible to receive at least one of SoC according to local regulations/approvals.
• Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

• Participant must be \> 18 years of age at the time of signing the ICF.
• Histologically confirmed MIUC of the bladder or upper tract.
• Completed R0 radical resection 28 to 120 days before randomisation, with negative margins and no residual or metastatic disease.
• Pathologic evidence of urothelial carcinoma at high-risk of recurrence and
  • not received neoadjuvant therapy and has pT3-pT4aN0, or any pT with pN+ stage
  • completed neoadjuvant treatment and has ypT2-ypT4a, or any ypT with ypN+ stage
• No evidence of disease at screening,
• ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation.
• Minimum life expectancy of \> 12 weeks at time of screening.
• An archival surgical tumour sample must be available pre-randomisation for central testing.
• Adequate organ and bone marrow function within 28 days before randomisation.