TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer.

Background: Standard of care (SoC) for patients with advanced triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score ⩾ 10) is chemotherapy plus anti-PD-(L)1 inhibitors; however, prognosis and survival for most patients is poor. Datopotamab deruxtecan (Dato-DXd), a novel antibody-drug conjugate comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a plasma-stable, cleavable, tetrapeptide-based linker, has shown preliminary activity as mono or combination therapy in advanced/metastatic TNBC. Objectives: TROPION-Breast05 is an ongoing randomized, open-label, multicenter phase III study. The primary objective is to demonstrate the superiority of Dato-DXd in combination with durvalumab (an anti-PD-L1 antibody) versus SoC treatment in patients with PD-L1-high locally recurrent inoperable or metastatic TNBC. Methods and design: Patients (⩾18 years) will be randomized 1:1 to receive Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) or investigator's choice of chemotherapy (ICC; paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) plus pembrolizumab (200 mg IV Q3W). In selected countries, patients will also be randomized (1:1:1) to a third arm of Dato-DXd monotherapy. The primary study endpoint is progression-free survival (PFS) per blinded independent central review (Dato-DXd plus durvalumab arm vs ICC plus pembrolizumab arm). Overall survival is a key secondary endpoint; other secondary endpoints include PFS (investigator-assessed), objective response rate, duration of response, clinical benefit rate at Week 24 (all assessed in the Dato-DXd plus durvalumab arm vs ICC plus pembrolizumab arm), patient-reported outcomes, and safety. Ethics: The study is approved by independent ethics committees or institutional review boards at each study site. All patients will provide written informed consent. Discussion: TROPION-Breast05 will assess the potential role of Dato-DXd with or without durvalumab in patients with PD-L1-high advanced or metastatic TNBC. The findings of this trial could lead to a new treatment option for these patients. Trial registration: ClinicalTrials.gov identifier: NCT06103864 (Date of registration: 27 October 2023).