A phase 3 trial evaluated trastuzumab deruxtecan (DS-8201) versus chemotherapy in patients with HER2-low metastatic breast cancer. The study enrolled 557 patients, with 494 (88.7%) having hormone receptor-positive disease and 63 (11.3%) hormone receptor-negative. In the hormone receptor-positive cohort, trastuzumab deruxtecan significantly improved progression-free survival (10.1 vs. 5.4 months) and overall survival (23.9 vs. 17.5 months) compared to chemotherapy. Among all patients, trastuzumab deruxtecan also showed better progression-free survival (9.9 vs. 5.1 months) and overall survival (23.4 vs. 16.8 months). Adverse events occurred in 52.6% of trastuzumab deruxtecan recipients and 67.4% of chemotherapy recipients, with interstitial lung disease or pneumonitis occurring in 12.1% of trastuzumab deruxtecan patients. The drug showed significant efficacy across subgroups, including those with HER2 IHC scores of 1+ and 2+ with ISH-negative results. Trastuzumab deruxtecan also demonstrated a higher response rate (52.6% vs. 16.3%) and longer duration of response compared to chemotherapy. The safety profile was similar to that of HER2-positive breast cancer patients, with neutropenia being the most common grade 3 or higher adverse event. Interstitial lung disease remains a key risk, but management guidelines were followed. The results suggest that trastuzumab deruxtecan is a superior treatment option for HER2-low metastatic breast cancer, regardless of hormone receptor status. The study was funded by Daiichi Sankyo and AstraZeneca.A phase 3 trial evaluated trastuzumab deruxtecan (DS-8201) versus chemotherapy in patients with HER2-low metastatic breast cancer. The study enrolled 557 patients, with 494 (88.7%) having hormone receptor-positive disease and 63 (11.3%) hormone receptor-negative. In the hormone receptor-positive cohort, trastuzumab deruxtecan significantly improved progression-free survival (10.1 vs. 5.4 months) and overall survival (23.9 vs. 17.5 months) compared to chemotherapy. Among all patients, trastuzumab deruxtecan also showed better progression-free survival (9.9 vs. 5.1 months) and overall survival (23.4 vs. 16.8 months). Adverse events occurred in 52.6% of trastuzumab deruxtecan recipients and 67.4% of chemotherapy recipients, with interstitial lung disease or pneumonitis occurring in 12.1% of trastuzumab deruxtecan patients. The drug showed significant efficacy across subgroups, including those with HER2 IHC scores of 1+ and 2+ with ISH-negative results. Trastuzumab deruxtecan also demonstrated a higher response rate (52.6% vs. 16.3%) and longer duration of response compared to chemotherapy. The safety profile was similar to that of HER2-positive breast cancer patients, with neutropenia being the most common grade 3 or higher adverse event. Interstitial lung disease remains a key risk, but management guidelines were followed. The results suggest that trastuzumab deruxtecan is a superior treatment option for HER2-low metastatic breast cancer, regardless of hormone receptor status. The study was funded by Daiichi Sankyo and AstraZeneca.