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).

This Phase 2/3 study evaluates datopotamab deruxtecan (Dato-DXd) in combination with platinum-based chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who have progressed during or after treatment with enfortumab vedotin plus pembrolizumab. The Phase 2 primary objective is to evaluate the relative efficacy of Dato-DXd 4 mg/kg plus platinum therapy compared with Dato-DXd 6 mg/kg plus platinum therapy, as measured by overall response rate (ORR) assessed by investigator. This dose-finding component is clinically relevant for establishing the optimal Dato-DXd dosing regimen in this treatment setting. The Phase 3 primary objectives are to compare the efficacy of Dato-DXd plus platinum therapy with gemcitabine plus platinum therapy, assessed by progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) and by overall survival (OS). These endpoints are critical for determining whether this antibody-drug conjugate combination offers superior clinical benefit compared to standard chemotherapy in this previously treated patient population.

The secondary objectives include:

• Phase 2: Further evaluation of the relative efficacy of Dato-DXd 4 mg/kg plus platinum therapy and Dato-DXd 6 mg/kg plus platinum therapy

• Phase 2: Assessment of the relative safety and tolerability of Dato-DXd 4 mg/kg plus platinum therapy and Dato-DXd 6 mg/kg plus platinum therapy

• Phase 2: Assessment of the immunogenicity of Dato-DXd

• Phase 2: Evaluation of the pharmacokinetics (PK) of Dato-DXd and DXd and exposure-response relationships for efficacy and safety

• Phase 3: Further evaluation of the efficacy of Dato-DXd plus platinum therapy compared with gemcitabine plus platinum therapy

• Phase 3: Evaluation of the safety and tolerability of Dato-DXd plus platinum therapy compared with gemcitabine plus platinum therapy

• Phase 3: Assessment of the immunogenicity of Dato-DXd

• Phase 3: Evaluation of the impact of Dato-DXd plus platinum therapy compared with gemcitabine plus platinum therapy on disease-related symptoms as measured by patient-reported outcome (PRO) instruments

• Phase 3: Evaluation of the impact of Dato-DXd plus platinum therapy compared with gemcitabine plus platinum therapy on overall health as measured by PRO instruments

• Phase 3: Evaluation of the impact of Dato-DXd plus platinum therapy compared with gemcitabine plus platinum therapy on role and physical functioning as measured by PRO instruments

The clinical trial enrolled a total of **306 participants** diagnosed with **locally advanced or metastatic urothelial carcinoma** of the bladder, renal pelvis, ureter, or urethra. The study population included both **male and female** adults aged **18 years and older**. Participants were selected based on histologically or cytologically confirmed disease that was unresectable, locally advanced, or metastatic. Eligible individuals had experienced radiographic progression or relapse during or after first-line therapy with **enfortumab vedotin** and **pembrolizumab**, or had discontinued this regimen due to toxicity followed by disease progression. Participants were required to have measurable disease according to **RECIST version 1.1** criteria and an **ECOG performance status** of 0 or 1, indicating good functional capacity. Eligibility also required participants to be suitable candidates for **cisplatin-** or **carboplatin-containing chemotherapy** as determined by the investigator. Essential laboratory parameters included adequate bone marrow, renal, hepatic, and blood clotting function. A tumor tissue sample from archival tissue or a newly obtained pretreatment biopsy was mandatory for exploratory biomarker testing. The trial included a vulnerable population as part of its study design.

This is a randomized, open-label, Phase 2/3 clinical trial evaluating the efficacy and safety of **datopotamab deruxtecan** in combination with platinum-based chemotherapy compared to **gemcitabine** plus platinum-based chemotherapy in participants with **locally advanced or metastatic urothelial carcinoma** who have progressed during or after treatment with enfortumab vedotin plus pembrolizumab. The trial employs a two-phase design, with Phase 2 serving to evaluate the relative efficacy of two different doses of datopotamab deruxtecan (4 mg/kg and 6 mg/kg) in combination with platinum therapy as measured by **overall response rate** assessed by investigator. Phase 3 is designed to compare the efficacy of the selected dose of datopotamab deruxtecan plus platinum therapy with gemcitabine plus platinum therapy, with co-primary endpoints of **progression-free survival** assessed by **Blinded Independent Central Review** using RECIST Version 1.1 criteria and **overall survival**. The trial duration is estimated to span from December 2025 to April 2030.

Eligible participants must be adults aged 18 years or older with histologically or cytologically confirmed unresectable locally advanced or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Participants must have experienced radiographic progression or relapse during or after first-line treatment with enfortumab vedotin and pembrolizumab, or have discontinued this regimen due to toxicity followed by disease progression. Additional inclusion criteria require measurable disease per RECIST Version 1.1 assessed by **computed tomography** or **magnetic resonance imaging**, an **ECOG performance status** of 0 or 1, and eligibility to receive cisplatin- or carboplatin-containing chemotherapy as determined by the investigator. Participants must provide tumor tissue samples for exploratory **biomarker** testing and demonstrate adequate bone marrow, renal, hepatic, and blood clotting function based on baseline laboratory assessments.

The investigational medicinal products include datopotamab deruxtecan, an **antibody drug conjugate**, administered as a **solution for infusion** via **intravenous infusion** at doses of either 4 mg/kg or 6 mg/kg, with a maximum daily dose of 6 mg/kg, maximum total dose of 540 mg, and maximum treatment period of 120 weeks. The comparator arm consists of gemcitabine administered at a maximum daily dose of 1000 mg/m² combined with either **cisplatin** at a maximum daily dose of 70 mg/m² or **carboplatin** at a maximum daily dose of 750 mg, all administered as solutions for infusion via intravenous infusion, with a maximum treatment period of 5 weeks for the comparator agents. All medicinal products are delivered through intravenous infusion routes.

Secondary endpoints for Phase 2 include **duration of response**, progression-free survival assessed by investigator, overall survival, **time to response**, **disease control rate**, and safety assessments encompassing incidence of **treatment-emergent adverse events**, **serious adverse events**, **adverse events of special interest**, deaths, and changes from baseline in vital signs, clinical laboratory parameters, **electrocardiogram** parameters, **echocardiography** or **multigated acquisition scan** findings, and ophthalmologic findings. Additional secondary endpoints include evaluation of **anti-drug antibody** incidence and characterization of population **pharmacokinetics** of datopotamab deruxtecan and its payload DXd, including the relationship between exposure and efficacy and safety endpoints. For Phase 3, secondary endpoints include progression-free survival assessed by investigator, overall response rate assessed by both Blinded Independent Central Review and investigator, duration of response, time to response, disease control rate, safety assessments similar to Phase 2, anti-drug antibody incidence, and **patient-reported outcomes** including **time to confirmed deterioration** and mean change from baseline in urinary symptoms as measured by the EORTC-QLQ-BLM30, **global health status** and **quality of life** as measured by the EORTC-QLQ-C30, and physical and role functioning domains from the EORTC-QLQ-C30.

Participant involvement in the study includes a screening visit to assess eligibility criteria, followed by randomization to one of the treatment arms. Study visits occur throughout the treatment period for administration of study medication, tumor assessments per RECIST Version 1.1 criteria, safety monitoring, collection of blood samples for laboratory assessments and pharmacokinetic analysis, and completion of patient-reported outcome questionnaires. Tumor imaging assessments are conducted at regular intervals by both investigator and, in Phase 3, by Blinded Independent Central Review to evaluate disease progression. Safety assessments at each visit include monitoring for adverse events, vital signs, clinical laboratory parameters, electrocardiogram evaluations, and periodic cardiac and ophthalmologic examinations. The end-of-study visit occurs upon completion of treatment or early discontinuation, with participants continuing to be followed for survival status. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, participant withdrawal of consent, investigator decision, pregnancy, or protocol deviation. The total duration of participant involvement varies depending on individual response to treatment and tolerability, with the potential for extended treatment in the datopotamab deruxtecan arms up to 120 weeks and shorter treatment periods in the comparator arms.

The experimental medication **Datopotamab deruxtecan** (DS-1062) is an **antibody drug conjugate** administered as a **solution for infusion** via **intravenous infusion**. The product is supplied by DAIICHI SANKYO, INC. and contains datopotamab deruxtecan as the active substance of protein origin. In the Phase 2 portion of the study, two dosing regimens are evaluated: **4 mg/kg** and **6 mg/kg**, administered in combination with platinum therapy. The maximum daily dose is **6 mg/kg**, with a maximum total dose of **540 mg** per treatment cycle. The maximum treatment period extends to **120 weeks**. Datopotamab deruxtecan is administered as part of combination therapy with either carboplatin or cisplatin.

**Gemcitabine** is utilized as a **comparator treatment** in this study and is supplied as Ribozar 1 g powder for preparation of **solution for infusion** by HIKMA FARMACÊUTICA (PORTUGAL), S.A. The active substance is gemcitabine, a chemical compound with ATC code L01BC05. Gemcitabine is administered via **intravenous infusion** at a maximum daily dose of **1000 mg/m²**. The maximum treatment period for gemcitabine administration is **5 weeks**. Gemcitabine is administered in combination with either carboplatin or cisplatin as part of the standard comparator regimen.

**Cisplatin** serves as a **comparator treatment** and is provided as Cisplatin Hikma 1 mg/ml concentrate for preparation of **solution for infusion** by HIKMA FARMACÊUTICA (PORTUGAL), S.A. The active substance is cisplatin, a chemical compound with ATC code L01XA01. Administration is performed via **intravenous infusion** with a maximum daily dose of **70 mg/m²**. The maximum treatment period is **5 weeks**. Cisplatin is used in combination with either datopotamab deruxtecan or gemcitabine, depending on the treatment arm assignment.

**Carboplatin** functions as a **comparator treatment** and is supplied as Carboplatin Hikma 10 mg/ml concentrate for preparation of **solution for infusion** by HIKMA FARMACÊUTICA (PORTUGAL), S.A. The active substance is carboplatin, a chemical compound with ATC code L01XA02. The medication is administered via **intravenous infusion** at a maximum daily dose of **750 mg**. The maximum treatment period for carboplatin is **5 weeks**. Carboplatin is administered in combination with either datopotamab deruxtecan or gemcitabine as part of the platinum-based chemotherapy backbone, serving as an alternative to cisplatin based on clinical considerations.

Efficacy will be assessed through distinct parameters for Phase 2 and Phase 3 of the trial. In Phase 2, the primary efficacy endpoint is overall response rate (ORR), defined as the proportion of participants with a best overall response of confirmed complete response or confirmed partial response, as assessed by investigator using RECIST Version 1.1 criteria. Secondary efficacy endpoints in Phase 2 include duration of response (DoR), measured from the date of first documentation of objective tumor response to the date of first documented radiographic disease progression or death due to any cause in responding participants, progression-free survival (PFS), defined as the time interval from randomization to first documented radiographic disease progression or death, overall survival (OS), defined as the time from randomization to death due to any cause, time to response (TTR), measured from randomization to first documentation of objective tumor response in responding participants, and disease control rate (DCR), defined as the proportion of participants with confirmed complete response, confirmed partial response, or stable disease. All Phase 2 efficacy assessments utilize investigator assessment of tumor scans according to RECIST Version 1.1 criteria.

In Phase 3, the co-primary efficacy endpoints are PFS, determined by Blinded Independent Central Review (BICR) assessment of tumor scans using RECIST Version 1.1 criteria and defined as the time from randomization to first documented radiographic disease progression or death, and OS, defined as the time from randomization to death due to any cause. Secondary efficacy endpoints in Phase 3 include PFS assessed by investigator, ORR assessed by both BICR and investigator using RECIST Version 1.1 criteria, DoR assessed by both BICR and investigator, TTR assessed by both BICR and investigator, and DCR assessed by both BICR and investigator. Additional secondary endpoints include time to confirmed deterioration (TTCD) and mean change from baseline in the urinary symptoms subscale of the EORTC-QLQ-BLM30, TTCD and mean change from baseline in global health status/quality of life as measured by the GHS/QoL scale from EORTC-QLQ-C30, and TTCD and mean change from baseline in physical and role functioning as measured by the physical functioning and role functioning domains from EORTC-QLQ-C30.