DESTINY-Breast11: Neoadjuvant T-DXd-THP safe and efficacious in high-risk HER2+ early BC

Neoadjuvant trastuzumab deruxtecan (T-DXd) followed by trastuzumab plus paclitaxel and pertuzumab (THP) was more efficacious and less toxic than dose-dense doxorubicin plus cyclophosphamide followed by THP (ddAC-THP) for patients with newly diagnosed high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC).

The randomised, global, multicentre, open-label, phase 3 DESTINY-Breast11 trial (NCT05113251) enrolled 927 participants with newly diagnosed high-risk HER2-positive early BC. Participants were randomised 1:1:1 to receive 4 cycles of T-DXd followed by 4 cycles of THP, 4 cycles of ddAC followed by 4 cycles of THP, or 8 cycles of T-DXd. The primary endpoint was pathologic complete response (pCR) assessed by blinded central review. Prof. Nadia Harbeck (Ludwig-Maximilians University Hospital, Germany) presented the key findings [1].

T-DXd-THP demonstrated superior pCR rates versus ddAC-THP (67.3% vs 56.3%; delta 11.2; 95% CI 4.0-18.3; P=0.003). “This result was consistent across HR-positive and HR-negative subgroups,” noted Prof. Harbeck. In addition, 81.3% of the participants in the T-DXd-THP arm achieved residual invasive breast cancer (RBC) 0 or 1 compared with 69.1% in the ddAC-THP arm.

Serious adverse events occurred less frequently with T-DXd-THP than with ddAC-THP (10.6% vs 20.2%). “Left ventricular dysfunction was observed in 6.1% of the participants in the ddAC-THP arm and in only 1.3% of the participants in the T-DXd-THP arm,” Prof. Harbeck highlighted. Grade ≥3 haematologic toxicity and fatigue were also more common in the ddAC-THP arm. Drug-related adjudicated interstitial lung disease/pneumonitis was an adverse event of special interest in this study. The rates were similar across the two arms, with 4.4% in the T-DXd-THP arm and 5.1% in the ddAC-THP arm.

“These results indicate that T-DXd-THP is a more efficacious and less toxic neoadjuvant treatment option for patients with high-risk HER2-positive early BC than ddAC-THP,” concluded Prof. Harbeck.

1. Harbeck N, et al. DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel + trastuzumab + pertuzumab vs ddAC-THP for high-risk HER2+ early breast cancer. 291O. European Society for Medical Oncology (ESMO) Congress, 17-21 October 2025, Berlin, Germany.

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Posted on 15 December 20257 January 2026