Daiichi Sankyo and AstraZeneca have announced that the first patient has been dosed in the Phase 3 TROPION-Urothelial04 trial, evaluating Datroway (datopotamab deruxtecan) in patients with Muscle-Invasive Urothelial Cancer (MIUC) who are at high risk of recurrence following radical surgical resection.

The global trial will assess Datroway in combination with rilvegostomig, Datroway monotherapy, and current standard-of-care treatments. The study is designed to determine whether these approaches can improve outcomes for patients whose disease remains at significant risk of returning despite surgery and existing adjuvant treatment options.

Datroway is a TROP2-directed Antibody-Drug Conjugate (ADC) discovered by Daiichi Sankyo and jointly developed and commercialised with AstraZeneca. Rilvegostomig is AstraZeneca’s investigational PD-1/TIGIT dual checkpoint inhibitor bispecific antibody.

MIUC accounts for approximately 30 percent of urothelial cancer cases and is an aggressive form of the disease in which cancer has invaded the muscle layer of the bladder or other relevant urinary tract structures. Although adjuvant immunotherapy is an established treatment approach, a substantial proportion of patients continue to face the risk of disease recurrence, highlighting the need for additional therapies.

The TROPION-Urothelial04 study is a global, multicentre, three-arm, open-label Phase 3 trial expected to enrol approximately 915 patients across Asia, Europe, North America, Oceania and South America. Participants will be randomised in a 2:1:2 ratio to receive either Datroway plus rilvegostomig, Datroway alone, or an investigator-selected standard-of-care treatment.

The standard-of-care arm will include durvalumab monotherapy, nivolumab monotherapy, or enfortumab vedotin plus pembrolizumab. The study will include patients with high-risk MIUC, including those with residual disease following neoadjuvant therapy and radical surgery, as well as patients with high-risk disease following surgery without prior neoadjuvant treatment.

The primary endpoint is Disease-Free Survival (DFS) assessed by investigators for Datroway plus rilvegostomig compared with standard of care. Key secondary endpoints include DFS assessed by blinded independent central review, disease-specific survival, non-urothelial tract recurrence-free survival, distant metastasis-free survival, patient-reported outcomes, overall survival and safety.

The trial builds on earlier clinical research evaluating Datroway in urothelial cancer. Daiichi Sankyo and AstraZeneca are also investigating Datroway in combination with platinum-based chemotherapy in the Phase 2/3 TROPION-Urothelial03 trial for patients with metastatic urothelial carcinoma whose disease has progressed during or after treatment with enfortumab vedotin plus pembrolizumab.

Urothelial cancer is the most common form of bladder cancer, accounting for approximately 90 percent of cases. It can develop in the bladder as well as the upper urinary tract, including the renal pelvis and ureter. Globally, more than 635,000 bladder cancer cases were diagnosed in 2024.

TROP2, the target of Datroway, is broadly expressed across several solid tumours, including urothelial cancer. Its expression has also been associated with disease severity in patients with urothelial cancer, supporting continued investigation of TROP2-directed therapies in the disease.

Datroway uses Daiichi Sankyo’s proprietary DXd ADC technology. The ADC consists of a humanised anti-TROP2 monoclonal antibody linked to multiple topoisomerase I inhibitor payloads through cleavable tetrapeptide-based linkers. The technology is designed to deliver the cytotoxic payload directly to TROP2-expressing tumour cells.

Datroway is already approved in multiple countries and regions for certain patients with unresectable or metastatic triple-negative breast cancer, HR-positive/HER2-negative breast cancer and EGFR-mutated non-small cell lung cancer, depending on the market and indication.

The companies are conducting a broad global clinical development programme involving more than 20 trials evaluating Datroway across multiple cancer types, including lung, breast and urothelial cancers. The programme includes multiple Phase 3 studies investigating the ADC both as a monotherapy and in combination with other cancer treatments.

With TROPION-Urothelial04, Daiichi Sankyo and AstraZeneca are expanding the development of Datroway into an earlier-stage setting where reducing recurrence and improving long-term outcomes remain significant clinical priorities.