Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab+pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel+trastuzumab+pertuzumab (THP) versus dose-dense doxorubicin+cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3), HER2-positive disease.

This open-label, phase 3 trial (147 sites, 18 countries) randomised adults 1:1:1 to T-DXd (×8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). T-DXd-alone arm enrolment closed early following Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set).

gov: NCT05113251; recruitment closed.

Between 25/10/2021 and 12/03/2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43·0% (T-DXd, n=123), 67·3% (T-DXd-THP, n=216), and 56·3% (ddAC-THP, n=180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11·2% (95% CI, 4·0, 18·3; p=0·003), with benefit in hormone receptor-positive (61·4% [n/N=145/236] vs 52·3% [n/N=123/235]; ΔpCR 9·1% [95% CI, 0·2, 17·9]) and -negative (83·1% [n/N=69/83] vs 67·1% [n/N=57/85]; ΔpCR 16·1% [95% CI, 3·0, 28·8]) subgroups. Median EFS (T-DXd-THP vs ddAC-THP, maturity 4.5%) hazard ratio was 0·56 [95% CI, 0·26, 1·17]). Grade ≥3 AE (T-DXd, 22·6% [n=64]; T-DXd-THP, 37·5% [n=120]; ddAC-THP, 55·8% [n=174]), serious AE (T-DXd, 10·2% [n=29]; T-DXd-THP, 10·6% [n=34]; ddAC-THP, 20·2% [n=63]), and all-grade left-ventricular dysfunction (T-DXd, 0·7% [n=2]; T-DXd-THP, 1·3% [n=4]; ddAC-THP, 6·1% [n=19]) rates were lower for T-DXd and T-DXd-THP than ddAC-THP. All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms (T-DXd, 4·9% [n=14]; T-DXd-THP, 4·4% [n=14]; ddAC-THP, 5·1% [n=16]). Three treatment-related deaths occurred (T-DXd-THP, 0·3% [n=1]; ddAC-THP, 0·6% [n=2]).

Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.