The Destiny-Breast09 trial findings demonstrated improved progression-free survival (PFS) with T-DXd plus pertuzumab compared with the standard Cleopatra regimen in first-line HER2-positive metastatic breast cancer. However, interpretation requires careful consideration of study design nuances, as many patients in the control arm received only trastuzumab plus pertuzumab maintenance after taxane induction rather than continuous chemotherapy. Patient selection for frontline T-DXd plus pertuzumab should focus on those requiring rapid response or having high-risk features such as extensive disease, visceral involvement, or central nervous system metastases where T-DXd demonstrates particular activity. Treatment personalization must balance the high efficacy of frontline T-DXd against potential overtreatment and the reality that up to 50% of patients may not receive subsequent therapies due to clinical deterioration. Quality-of-life considerations, patient preferences, and individual risk factors, including disease-free interval, tumor burden, and genomic characteristics, should guide treatment selection.