The FDA’s simultaneous neoadjuvant and adjuvant approval of fam-trastuzumab deruxtecan-nxki (Enhertu) for HER2-positive stage II-III breast cancer represents the first major protocol shift since the introduction of dual HER2 blockade. Phase III DESTINY-Breast11 (RCT, n=624) demonstrated a 67.3% pathologic complete response rate with Enhertu followed by THP versus 56.3% for dose-dense AC-THP, establishing superiority in the preoperative setting. DESTINY-Breast05 (RCT, n=1,635) reported a 53% reduction in invasive disease-free survival events (HR 0.47) and 92.4% versus 83.7% 3-year iDFS, positioning the antibody-drug conjugate ahead of T-DM1 for residual disease. These large, industry-sponsored RCTs carry clear conflicts of interest via AstraZeneca/Daiichi Sankyo funding, yet the effect sizes exceed those seen in prior adjuvant escalations. What MedicalXpress omitted is the drug’s known interstitial lung disease signal (grade ≥3 rates 2-4% across trials), which may alter risk-benefit calculus for lower-risk stage II patients and necessitate new monitoring protocols. Real-world adoption will also hinge on reimbursement; current list price exceeds $15,000 per cycle, potentially widening disparities despite the curative intent highlighted by AstraZeneca executives. Cross-trial comparisons with KATHERINE and APHINITY suggest Enhertu could compress recurrence rates further, but head-to-head data versus optimized THP sequences are still maturing.