Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial

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. 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%. T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2%, P = 0.003], with benefit in hormone receptor (HR)-positive [61.4% (n/N = 145/236) versus 52.3% (n/N = 123/235); difference in pCR 9.1%  and HR-negative [83.1% (n/N = 69/83) versus 67.1% (n/N = 57/85); ΔpCR 16.1%] subgroups. Median EFS (T-DXd-THP versus ddAC-THP, maturity 4.5%) hazard ratio was 0.56. Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.