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.
Keywords: HR-low/HER2− breast cancer; antibody-drug conjugate; datopotamab deruxtecan; durvalumab; neoadjuvant; triple-negative breast cancer.
TROPION-Breast04: a clinical study comparing datopotamab deruxtecan (Dato-DXd) plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery, versus standard of care treatment in people with triple-negative breast cancer (TNBC) or hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2−) breast cancer who have not received previous treatment People with TNBC have neither estrogen receptors and/or progesterone receptors nor a protein called HER2 expressed on their cancer cells. Standard treatment for early-stage TNBC that has not spread to other parts of the body and can be removed by surgery is pembrolizumab (a drug that makes cancer cells more susceptible to being killed by the immune system) plus chemotherapy before surgery, and pembrolizumab after surgery. People with HR-low/HER2− breast cancer (BC) do not have HER2 but have low levels of estrogen/progesterone receptors on their cancer cells and may be treated similarly to those with TNBC. Some people with high-risk early-stage TNBC or HR-low/HER2− BC experience a recurrence of their cancer after standard treatment. Therefore, new therapies that stop cancer returning and improve long-term outcomes are needed. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate that consists of an antibody (datopotamab) and an anticancer drug payload (DXd), joined via a stable cleavable linker. In people with TNBC that has spread to other parts of the body, promising outcomes have been observed with Dato-DXd alone or in combination with durvalumab (a drug that makes cancer cells more susceptible to being killed by the immune system). In the TROPION-Breast04 study, approximately 1700 people with early-stage TNBC or HR-low/HER2– BC who have not received previous treatment will be randomly assigned in equal numbers to receive Dato-DXd plus durvalumab followed by surgery and durvalumab with or without chemotherapy, or pembrolizumab plus chemotherapy followed by surgery and pembrolizumab with or without chemotherapy. TROPION-Breast04 will show if Dato-DXd plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery can help people with early-stage TNBC and HR-low/HER2– BC live longer without their cancer returning versus pembrolizumab plus chemotherapy before surgery followed by pembrolizumab with or without chemotherapy.
© The Author(s), 2025.