Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial

Background: Prognosis is poor, and treatment options are limited for patients with previously untreated, advanced triple-negative breast cancer (TNBC), especially for those who are not candidates for immunotherapy. Patients and methods: In the randomised, open-label, phase III TROPION-Breast02 trial, patients with previously untreated, locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option were randomly assigned 1:1 to datopotamab deruxtecan (Dato-DXd; 6 mg/kg intravenously every 3 weeks) or investigator's choice of chemotherapy. Randomisation was stratified by geographic location, disease-free interval, and programmed cell death ligand-1 status. Dual primary endpoints were progression-free survival (PFS; blinded independent central review per RECIST version 1.1) and overall survival (OS). Efficacy analyses were performed in the intention-to-treat population. Safety analyses included all patients who received ≥1 dose of study treatment. Results: Between 16 May 2022 and 11 June 2024, 644 patients were randomly assigned to receive Dato-DXd (n = 323) or chemotherapy (n = 321). Median PFS was 10.8 months [95% confidence interval (CI) 8.6-13.0] with Dato-DXd and 5.6 months (95% CI 5.0-7.0) with chemotherapy [hazard ratio 0.57 (99% CI 0.44-0.73); P < 0.0001]. Median OS was 23.7 months (95% CI 19.8-25.6) and 18.7 months (95% CI 16.0-21.8) with Dato-DXd and chemotherapy, respectively [hazard ratio 0.79 (95.01% CI 0.64-0.98); P = 0.029]. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in 105 (33%) and 89 (29%) patients who received Dato-DXd and chemotherapy, respectively, and TRAEs led to treatment discontinuation in 14 (4%) and 23 (7%) patients. There were no treatment-related deaths in either arm. Conclusions: Dato-DXd demonstrated significantly improved PFS and OS versus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. Safety was consistent with the known profile for Dato-DXd.