The DESTINY-Breast03 trial compared the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DMI) in patients with HER2-positive metastatic breast cancer who had previously received taxane and trastuzumab. The updated analysis, with a median follow-up of 41 months, showed that T-DXd continued to demonstrate superior efficacy over T-DMI. The median progression-free survival (PFS) was 29.0 months with T-DXd compared to 7.2 months with T-DMI, and the 36-month PFS rate was 45.7% versus 12.4%. The median overall survival (OS) was 52.6 months with T-DXd versus 42.7 months with T-DMI. Treatment-emergent adverse events were consistent with previous analyses, and no new instances of grade ≥3 interstitial lung disease or pneumonitis occurred. The safety profile of T-DXd remained manageable, with no cumulative toxicities observed over longer follow-up. These findings support the continued use of T-DXd as a guideline-recommended treatment for this patient population.The DESTINY-Breast03 trial compared the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DMI) in patients with HER2-positive metastatic breast cancer who had previously received taxane and trastuzumab. The updated analysis, with a median follow-up of 41 months, showed that T-DXd continued to demonstrate superior efficacy over T-DMI. The median progression-free survival (PFS) was 29.0 months with T-DXd compared to 7.2 months with T-DMI, and the 36-month PFS rate was 45.7% versus 12.4%. The median overall survival (OS) was 52.6 months with T-DXd versus 42.7 months with T-DMI. Treatment-emergent adverse events were consistent with previous analyses, and no new instances of grade ≥3 interstitial lung disease or pneumonitis occurred. The safety profile of T-DXd remained manageable, with no cumulative toxicities observed over longer follow-up. These findings support the continued use of T-DXd as a guideline-recommended treatment for this patient population.