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Datopotamab deruxtecan plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin for advanced or metastatic urothelial carcinoma

A Randomized, Open-Label, Phase 2/3 Study of Datopotamab Deruxtecan (Dato-DXd) Plus Carboplatin or Cisplatin Versus Gemcitabine Plus Carboplatin or Cisplatin in Participants With Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC) Who Progressed During or After Enfortumab Vedotin (EV) Plus Pembrolizumab Combination Treatment TROPION-Urothelial03 (TU03)

Phase2; Phase3 Interventional Daiichi Sankyo · NCT07129993

This trial will test whether datopotamab deruxtecan with carboplatin or cisplatin works better than gemcitabine with carboplatin or cisplatin for people with advanced urothelial carcinoma who progressed during or after enfortumab vedotin plus pembrolizumab.

Quick facts

PhasePhase2; Phase3
Study typeInterventional
Enrollment630 (estimated)
Ages18 Years and up
SexAll
SponsorDaiichi Sankyo Industry-sponsored
Drugs / interventionspembrolizumab, chemotherapy, immunotherapy, radiation
Locations80 sites (Fullerton, California and 79 other locations)
Trial IDNCT07129993 on ClinicalTrials.gov

What this trial studies

This is a global, multicenter, randomized, open-label Phase 2/3 trial comparing an antibody‑drug conjugate (datopotamab deruxtecan) plus platinum chemotherapy to the standard gemcitabine plus platinum combination in locally advanced or metastatic urothelial carcinoma. The trial begins with a Phase 2 (part A) portion to measure preliminary activity and safety and to identify a recommended Phase 3 dose. If the Phase 2 data support proceeding, a larger randomized Phase 3 portion will follow to compare efficacy outcomes such as response rate, progression-free survival, and overall survival. Safety, tolerability, and tolerability with platinum backbones will be closely monitored across both parts.

Who should consider this trial

Good fit: Adults (≥18 years) with histologically or cytologically confirmed unresectable locally advanced or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra who progressed during or after enfortumab vedotin plus pembrolizumab are the intended candidates.

Not a fit: Patients with non-eligible histologies such as urachal, small cell, or adenocarcinoma, or those who cannot receive carboplatin or cisplatin, are unlikely to qualify or benefit from this trial.

Why it matters

Potential benefit: If successful, this approach could provide a new effective treatment option for patients who progress after enfortumab vedotin plus pembrolizumab, potentially improving response rates and survival.

How similar studies have performed: Other antibody‑drug conjugates, including enfortumab vedotin and sacituzumab govitecan, have shown activity in urothelial cancer and TROP2‑targeting ADCs have shown encouraging signals in early trials, but datopotamab deruxtecan in this specific post‑enfortumab/pembrolizumab setting remains under study.

Eligibility criteria

Show full inclusion / exclusion criteria 
Key Inclusion Criteria:

* Adult ≥18 years at the time the ICF is signed (if the legal age of consent is \> 18 years old, then follow the local regulatory requirements).
* Histologically or cytologically confirmed unresectable locally advanced (T4b, any N; or any T, N 2-3) or metastatic (any T, any N, M1) urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra.

Participants with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible if the histology is predominantly urothelial.

* Note 1: Urachal, small cell, and adenocarcinoma histology is not permitted.
* Note 2: Participants with la/mUC and a history of nonclinically active prostate cancer are allowed into the trial if:

  1. Participant does not have radiological metastasis of a proven prostate cancer.
  2. Participant with nonmetastatic prostate cancer do not have rising PSA (as determined using local testing by a validated or approved test method) defined as follows:

     • Increase in PSA within 2 consecutive measurements separated by at least 1 week (completed within 4 weeks prior to consent or within Screening) and neither of the measurements with an absolute value above 2 ng/mL.
  3. Participant does not currently receive androgen deprivation therapy for the treatment of prostate cancer. • Must provide tumor tissue sample from archival tissue or newly obtained pretreatment biopsy for exploratory biomarker testing. Tumor tissue sample should not be collected from a lesion that was irradiated unless documentation can be provided confirming that the tumor tissue was collected at least 3 months after radiation and the lesion increased/appeared since radiation occurred. Tumor tissue must be of sufficient quantity (as defined in the laboratory manual).

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  1. Archival tissue collected after the most recent anticancer treatment and within 12 months before the informed consent date is preferred. • Participant must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment. Participants eligible for cisplatin will receive cisplatin. If a participant received gemcitabine, carboplatin or cisplatin for early UC in the adjuvant/neoadjuvant setting, ≥1 year must have passed since the last dose of these chemotherapy prior to the first dose of trial intervention. Participants only receive carboplatin if they are ineligible for cisplatin. Participants are cisplatin-ineligible if they meet any of the following criteria:

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  1. GFR \<60 mL/min (GFR may be estimated by calculated CrCl using the Cockcroft-Gault formula, Modification of Diet in Renal Disease, or 24-hour urine)

     * Participants with a GFR \<60 mL/min but ≥50 mL/min but have no other cisplatin ineligibility criteria (items b, c, and d) may be considered cisplatin-eligible based on the investigator's clinical judgment.
  2. NCI-CTCAE Grade ≥2 audiometric hearing loss
  3. NCI-CTCAE Grade ≥2 peripheral neuropathy
  4. NYHA Class III heart failure • Must have experienced radiographic progression or relapse during or after 1L of EV and pembrolizumab.

Participant who discontinued EV and pembrolizumab in 1L due to toxicity are eligible if they have experienced disease progression following discontinuation. Participant who received EV (or other agents with a vedotin payload) plus PD 1/PD-L1 inhibitors in a neoadjuvant/adjuvant setting and progressed during treatment or within 12 months of treatment completion will also be considered for enrollment, after approval by the Sponsor's Medical Monitor or Sponsor's designee.

Key Exclusion Criteria:

* Has had prior systemic therapy other than the combination of EV and pembrolizumab for la/mUC. The following participants may be considered eligible after approval by the Sponsor's Medical Monitor or Sponsor's designee.

  a. Participant who progressed during or after treatments with assets that include either anti-Nectin 4 or vedotin payload (MMAE or other microtubule inhibitors) combined with PD1/PD-L1 inhibitors in 1L la/mUC.
* Treatment with any of the following:

  1. History of an allogeneic bone marrow or solid organ transplant.
  2. Concomitant treatment with any prohibited medications in this protocol.
  3. Prior TROP2 directed ADC therapy.
* Uncontrolled or significant cardiovascular disease, including:

  1. QTcF interval \>450 ms based on the average of triplicate 12-lead (ECG per local read) at Screening.
  2. Myocardial infarction within 6 months prior to randomization.
  3. Uncontrolled angina pectoris within 6 months prior to randomization.
  4. NYHA Class 3 or 4 congestive heart failure at Screening (See Section 10.3.2).
  5. Uncontrolled hypertension (resting systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg within 28 days before randomization that is not resolved despite maximal medical therapy).
* Has a 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.
* Has clinically severe pulmonary compromise as judged by the investigator resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior complete pneumonectomy.
* Toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet improved to NCI-CTCAE version 5.0 Grade ≤1 or baseline. Note: Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade \>2 for at least 3 months prior to randomization and managed with standard of care treatment) which the investigator deems related to previous anticancer therapy, comprised of (including but not limited to):

  1. Anticancer therapy-induced neuropathy
  2. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies which may include:
* Hypothyroidism/ hyperthyroidism
* Type I diabetes
* Hyperglycemia
* Adrenal insufficiency
* Adrenalitis c. Skin hypopigmentation (vitiligo)

Where this trial is running

Fullerton, California and 79 other locations

+30 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Urothelial CancerBladder CancerUrothelial CarcinomaDato-DXdTROPIONDS-1062aDatopotamab Deruxtecan
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.