TROPION-Breast04: a randomized phase III study of neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by adjuvant durvalumab versus standard of care in patients with treatment-naïve early-stage triple negative or HR-low/HER2- breast cancer.

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies. Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. Design: This is an ongoing, international, phase III, open-label, randomized controlled study. Methods and analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety. Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent. Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. The findings of this trial could lead to promising treatment options for these patients. Trial registration: ClinicalTrials.gov identifier: NCT06112379.