AZ, Daiichi Sankyo take Datroway-rilvegostomig combo into Phase III bladder cancer trial

Daiichi Sankyo and AstraZeneca have dosed the first patient in a Phase III trial of Datroway (datopotamab deruxtecan) plus rilvegostomig in high-risk muscle-invasive urothelial cancer (MIUC), moving the TROP2-directed ADC and PD-1/TIGIT bispecific combination into the adjuvant setting.

The TROPION-Urothelial04 trial is a global, three-arm, open-label Phase III study comparing datopotamab deruxtecan plus rilvegostomig, or datopotamab deruxtecan monotherapy, against standard-of-care adjuvant immunotherapy — AstraZeneca's Imfinzi (durvalumab), Bristol Myers Squibb's Opdivo (nivolumab), or Merck and Astellas Pharma's Padcev (enfortumab vedotin) plus Merck's Keytruda (pembrolizumab) — in patients with high-risk muscle-invasive urothelial cancer (MIUC) following radical surgical resection. The trial is designed to enroll approximately 915 patients across Asia, Europe, North America, Oceania, and South America, randomized 2:1:2 across the three arms. The primary endpoint is disease-free survival (DFS) assessed by investigator for the combination arm versus standard of care; overall survival is a key secondary endpoint.

Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate that delivers a topoisomerase I inhibitor payload (DXd) via cleavable linkers to tumor cells expressing TROP2, a protein broadly expressed in urothelial cancer and positively correlated with disease severity. Rilvegostomig simultaneously blocks PD-1 and TIGIT, two inhibitory checkpoints that limit anti-tumor T-cell activity.

Results from the TROPION-PanTumor03 Phase II trial, presented at ESMO 2025, showed datopotamab deruxtecan plus rilvegostomig produced a confirmed objective response rate of 68.2% and a disease control rate of 95.5% in cisplatin-ineligible, previously untreated patients with locally advanced or metastatic urothelial cancer. A separate Phase II/III trial, TROPION-Urothelial03, is evaluating datopotamab deruxtecan plus platinum-based chemotherapy in metastatic urothelial carcinoma following progression on enfortumab vedotin plus pembrolizumab.

Datroway is approved in more than 30 countries for HR-positive, HER2-negative metastatic breast cancer, and received US FDA approval in May 2026 for first-line metastatic triple-negative breast cancer in patients who are not candidates for PD-1/PD-L1 inhibitor therapy, based on the TROPION-Breast02 Phase III trial. It also holds US accelerated approval for EGFR-mutated non-small cell lung cancer. No TROP2-directed medicine is currently approved for urothelial cancer.

The adjuvant MIUC setting has seen substantial recent activity. Nivolumab received FDA approval in 2021 based on the CheckMate 274 trial; durvalumab gained approval in March 2025 for perioperative use based on the NIAGARA trial; and enfortumab vedotin plus pembrolizumab received perioperative approval in November 2025. Atezolizumab gained a ctDNA-guided adjuvant approval in May 2026. TROPION-Urothelial04 tests whether a TROP2-directed ADC combined with dual PD-1/TIGIT blockade can improve on these checkpoint-based standards, which leave a proportion of patients at continued recurrence risk.

The inclusion of enfortumab vedotin plus pembrolizumab among the permitted standard-of-care comparators raises the efficacy bar for the Datroway-based regimens following the combination's recent move into earlier-stage urothelial cancer. Daiichi Sankyo and AstraZeneca describe TROPION-Urothelial04 as their second pivotal trial in urothelial cancer, alongside the parallel development of a similar adjuvant strategy in early-stage non-small cell lung cancer via the TROPION-Lung12 trial.

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