The DESTINY-Breast04 trial evaluated the efficacy and safety of trastuzumab deruxtecan compared to physician's choice chemotherapy in patients with HER2-low metastatic breast cancer. The study included 557 patients, with 494 (88.7%) having hormone receptor-positive disease and 63 (11.3%) having hormone receptor-negative disease. Trastuzumab deruxtecan significantly improved progression-free survival (PFS) and overall survival (OS) compared to the physician's choice of chemotherapy, regardless of hormone receptor status. The median PFS was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group for hormone receptor-positive patients, and 9.9 months and 5.1 months, respectively, for all patients. The median OS was 23.9 months and 17.5 months for hormone receptor-positive patients, and 23.4 months and 16.8 months, respectively, for all patients. Adverse events were generally manageable, with a higher incidence of grade 3 or higher events in the trastuzumab deruxtecan group (52.6% vs. 67.4%). Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan. The results suggest that trastuzumab deruxtecan is a superior treatment option for patients with HER2-low metastatic breast cancer, offering longer PFS and OS compared to standard chemotherapy.The DESTINY-Breast04 trial evaluated the efficacy and safety of trastuzumab deruxtecan compared to physician's choice chemotherapy in patients with HER2-low metastatic breast cancer. The study included 557 patients, with 494 (88.7%) having hormone receptor-positive disease and 63 (11.3%) having hormone receptor-negative disease. Trastuzumab deruxtecan significantly improved progression-free survival (PFS) and overall survival (OS) compared to the physician's choice of chemotherapy, regardless of hormone receptor status. The median PFS was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group for hormone receptor-positive patients, and 9.9 months and 5.1 months, respectively, for all patients. The median OS was 23.9 months and 17.5 months for hormone receptor-positive patients, and 23.4 months and 16.8 months, respectively, for all patients. Adverse events were generally manageable, with a higher incidence of grade 3 or higher events in the trastuzumab deruxtecan group (52.6% vs. 67.4%). Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan. The results suggest that trastuzumab deruxtecan is a superior treatment option for patients with HER2-low metastatic breast cancer, offering longer PFS and OS compared to standard chemotherapy.