Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive, HER2-negative breast cancer: final overall survival analysis of the phase III TROPION-Breast01 study

BACKGROUND: The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report results from the final overall survival (OS) analysis. PATIENTS AND METHODS: Patients with inoperable/metastatic HR-positive/HER2-negative breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and had received one to two prior lines of chemotherapy in the inoperable/metastatic setting were randomly assigned in a 1 : 1 ratio to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS. RESULTS: At data cut-off, median follow-up was 22.8 months. OS for the Dato-DXd versus ICC arm did not reach statistical significance (hazard ratio 1.01, 95% confidence interval 0.83-1.22, P = 0.9445). Use of ADCs (trastuzumab deruxtecan and sacituzumab govitecan) as subsequent therapy was imbalanced: 12.3% in the Dato-DXd arm versus 24.0% in the ICC arm. Secondary efficacy endpoints (PFS by investigator assessment, objective response rate, duration of response, disease control rate at 12 weeks, time to first and second subsequent therapy or death, and time to second progression or death) continued to favor Dato-DXd at this final analysis. The overall safety profile of Dato-DXd remained favorable compared with ICC, and no new safety signals were observed with longer follow-up. CONCLUSIONS: TROPION-Breast01 met its dual primary endpoint of PFS by BICR. While there was no statistically significant improvement in the dual primary endpoint of OS with Dato-DXd versus ICC, subsequent ADC treatment may have affected OS results. The totality of efficacy and safety data supports Dato-DXd as a new treatment option for patients with previously treated, inoperable/metastatic HR-positive/HER2-negative breast cancer.