TROPION-Urothelial04: A New Test of Adjuvant Therapy in Muscle-Invasive Urothelial Cancer Begins

KEY FINDINGS

• Trial: TROPION-Urothelial04 (NCT07720284) - announced on 26 August 2026, the date the first patient was dosed.
• Target: Adjuvant treatment in high-risk muscle-invasive urothelial cancer (MIUC) after radical resection.
• Design: A three-arm, global, open-label phase 3 trial; approximately 915 patients, 2:1:2 randomization.
• Experimental arms: Datopotamab deruxtecan plus rilvegostomig, and datopotamab deruxtecan monotherapy.
• Control arm: Current standard of care at investigator's choice - nivolumab, durvalumab, or enfortumab vedotin plus pembrolizumab.
• Primary endpoint: Investigator-assessed disease-free survival (DFS); estimated primary completion September 2030.

Background: The Expanding but Still Insufficient Horizon of Perioperative Therapy

Muscle-invasive urothelial cancer is a disease that offers a chance of oncological cure with radical cystectomy or nephroureterectomy, yet retains a high risk of recurrence. Although neoadjuvant platinum-based chemotherapy followed by radical surgery is the standard approach, recurrence rates remain unacceptably high in patients with pathologically advanced stage (pT3-pT4a) or lymph node-positive disease.

The past five years have seen three important turning points in the adjuvant and perioperative setting:

• CheckMate 274: Adjuvant nivolumab after radical surgery showed a significant disease-free survival benefit compared with placebo (N Engl J Med 2021).
• NIAGARA: Perioperative durvalumab with gemcitabine-cisplatin received FDA approval in March 2025.
• KEYNOTE-B15/EV-304: The perioperative enfortumab vedotin plus pembrolizumab regimen entered practice with FDA approval in July 2026.

Despite this, a substantial proportion of patients still relapse. The clinical question posed by TROPION-Urothelial04 is precisely this: can a TROP2-targeted antibody-drug conjugate, alone or combined with dual checkpoint inhibition, provide additional benefit on top of the best available adjuvant options?

Note: This is not a phase 3 trial with reported results; it is a newly initiated phase 3 trial. The data presented below reflect the study design and scientific rationale, not efficacy results.

Study Design

Eligibility Criteria

Patients must have undergone R0 radical resection with negative surgical margins and must have no evidence of residual or metastatic disease at the time of inclusion.

• Those not receiving neoadjuvant therapy: pathological stage pT3-pT4aN0 or node-positive disease at any pT stage.
• Those receiving neoadjuvant therapy: ypT2-ypT4a or node-positive disease at any ypT stage.

The Molecules: Why TROP2 and Why PD-1/TIGIT?

Datopotamab deruxtecan (Datroway)

An antibody-drug conjugate in which a humanised monoclonal antibody against TROP2 is linked to the topoisomerase I inhibitor DXd. TROP2 is a surface glycoprotein widely expressed in urothelial carcinoma, a property that makes it an attractive target for ADC platforms. The agent is already approved in the United States in certain breast cancer indications (unresectable/metastatic triple-negative and HR-positive/HER2-negative) and in EGFR-mutated advanced non-small cell lung cancer.

Rilvegostomig

An investigational bispecific antibody designed to block both the PD-1 and TIGIT signalling pathways simultaneously. It rests on the hypothesis that dual checkpoint inhibition may reverse T cell exhaustion more effectively than single-agent PD-1 blockade. The first signals for the combination in urothelial cancer came from the phase 2 TROPION-PanTumor03 trial in advanced/metastatic patients.

Important reminder: Neither datopotamab deruxtecan nor rilvegostomig is approved in the muscle-invasive urothelial cancer indication; both have investigational status in this setting.

Implications for Clinical Practice

1. The first ADC-based phase 3 comparison in the adjuvant setting

To date, adjuvant strategy in muscle-invasive disease has advanced largely along an immunotherapy axis. TROPION-Urothelial04 is one of the first large-scale trials to directly question the place of a targeted cytotoxic payload (an ADC) in this field.

2. The methodological value of the active control arm

The trial's use of three current standard regimens as control rather than placebo increases the direct applicability of the results to practice. However, this design also raises the bar for demonstrating superiority - achieving a meaningful DFS difference against a heterogeneous control arm is an ambitious goal.

3. Surgical quality and patient selection

The requirement for R0 resection and the strict eligibility criteria based on pathological stage once again underline that the success of adjuvant therapy is directly linked to surgical quality. In radical cystectomy, negative surgical margins and adequate lymph node dissection are the precondition defining the pool of patients who will benefit from systemic treatment.

4. Toxicity management

Because a substantial proportion of patients treated in the adjuvant setting will already be cured, the side effect profile is as decisive as efficacy. The risk of interstitial lung disease specific to the deruxtecan class and the immune-related adverse events of dual checkpoint blockade will be closely assessed in long-term follow-up.

Context: The Other Leg of the Same Platform

Datopotamab deruxtecan is also being evaluated in metastatic urothelial carcinoma. The phase 2/3 TROPION-Urothelial03 trial combines the agent with platinum-based chemotherapy against a gemcitabine plus platinum regimen in patients progressing during or after enfortumab vedotin and pembrolizumab therapy. The TROP2-targeted approach is thus being tested simultaneously in both the early and advanced stages of the disease.

Conclusion

The landscape of perioperative treatment in muscle-invasive urothelial cancer has changed fundamentally over the past two years; yet the risk of recurrence remains a real threat for a considerable proportion of patients. TROPION-Urothelial04 aims to close this gap by combining a TROP2-targeted antibody-drug conjugate with dual checkpoint blockade.

What the trial offers today is not a result but a well-designed question. A three-arm, global phase 3 design with an active control arm will ensure that the answer obtained is directly applicable clinically. Although results are expected towards 2030, the very fact that this trial has been launched is a sign that adjuvant strategy in uro-oncology is moving out of an immunotherapy monopoly onto multimodal ground.

References

• Daiichi Sankyo. TROPION-Urothelial04 phase 3 trial of Datroway initiated as adjuvant therapy in patients with high-risk muscle invasive urothelial cancer. Press release, 26 August 2026.
• Clarke H. Datopotamab deruxtecan enters phase 3 trial in high-risk muscle-invasive urothelial cancer. Urology Times, 26 August 2026.
• ClinicalTrials.gov. 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). NCT07720284.
• Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
• FDA. Durvalumab approval - muscle-invasive bladder cancer, 28 March 2025; pembrolizumab plus enfortumab vedotin approval, 10 July 2026.
• UroToday. ESMO 2025: Datopotamab deruxtecan + rilvegostomig - TROPION-PanTumor03.