Astrazeneca’s ENHERTU secures two new US approvals in HER2-positive early breast cancer

The US Food and Drug Administration has cleared AstraZeneca and Daiichi Sankyo’s ENHERTU® (fam-trastuzumab deruxtecan-nxki) for two additional indications in HER2-positive early breast cancer, drawing on data from the Phase III DESTINY-Breast11 and DESTINY-Breast05 trials. The decisions mark the medicine’s first move into curative-intent treatment and broaden its role across the spectrum of HER2-positive disease.

In the neoadjuvant (pre-surgery) setting, ENHERTU followed by a taxane, trastuzumab and pertuzumab (THP) is now approved for adults with HER2-positive Stage II or Stage III breast cancer. In the adjuvant (post-surgery) setting, it is approved for adults with HER2-positive breast cancer who still have residual invasive disease after receiving trastuzumab (with or without pertuzumab) and taxane-based therapy.

Shanu Modi, MD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, said: “HER2-positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence for patients as early as possible to achieve the best long-term outcomes. The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery. These two new indications in HER2-positive early breast cancer will evolve how we treat patients in these settings and support trastuzumab deruxtecan as a potential new standard of care in early-stage disease.”

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “HER2-positive early disease is considered highly curable, however up to one in four patients still experience disease recurrence, underscoring the need for new options in this setting. These approvals mark an important step forward, expanding the possibility of cure to more patients for the first time in many years and positioning ENHERTU as a foundational treatment in early breast cancer.”

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: “ENHERTU has redefined the treatment of HER2-expressing breast cancer with practice-changing data across six breast cancer indications in seven years. ENHERTU is now approved in the US across both early and metastatic HER2-positive breast cancer, accomplishing what we set out to achieve a little over a decade ago for patients at the start of our comprehensive clinical development program.”

Victoria Smart, Senior Vice President, Mission, Susan G. Komen, said: “Providing patients with early breast cancer more options to help prevent progression to metastatic disease can lead to improved outcomes. Progression and recurrence remain among the most significant unmet needs for those diagnosed with early breast cancer, and continued advances in treatment bring new hope to patients and families facing this disease.”

In the neoadjuvant DESTINY-Breast11 study, ENHERTU followed by THP delivered a pathologic complete response (pCR) rate of 67.3%, against 56.3% for dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP) — an absolute improvement of 11.2% (95% CI 3.9–18.3; p=0.003). At the time of the pCR analysis, event-free survival events had occurred in 29 patients (4.5%) and overall survival events in 12 patients (1.9%). The findings appeared in Annals of Oncology.

In the adjuvant DESTINY-Breast05 study, ENHERTU cut the risk of invasive disease recurrence or death by 53% versus trastuzumab emtansine (T-DM1) in patients with residual invasive disease after neoadjuvant therapy (HR 0.47; 95% CI 0.34–0.66; p<0.0001). Three-year invasive disease-free survival reached 92.4% on ENHERTU compared with 83.7% on T-DM1, with 51 events (6%) in the ENHERTU arm and 102 (12%) in the T-DM1 arm. Results were published in The New England Journal of Medicine. Data from both studies were presented at the 2025 ESMO Congress.

Following DESTINY-Breast05, trastuzumab deruxtecan has been added to the NCCN Clinical Practice Guidelines in Oncology as a Category 1 recommended adjuvant treatment for patients with HER2-positive early breast cancer who have residual disease and a high recurrence risk after preoperative therapy.

No new safety signals emerged from either trial. In DESTINY-Breast11, ENHERTU followed by THP produced overall drug-related adverse event (AE) and interstitial lung disease (ILD)/pneumonitis rates comparable to ddAC-THP, alongside lower rates of Grade 3 or higher AEs, serious AEs, AEs prompting treatment interruption, left ventricular dysfunction and haematological toxicities. In DESTINY-Breast05, overall drug-related AEs and Grade 3 or higher AEs occurred at similar rates across arms; adjudicated drug-related ILD/pneumonitis was reported in 9.6% of ENHERTU-treated patients and 1.6% of those on T-DM1, with most cases low grade. The ENHERTU arm recorded seven Grade 3 events and two Grade 5 (fatal) events.

Both US submissions were handled through Project Orbis, the FDA-led framework that enables concurrent oncology reviews across international regulators, and corresponding applications are progressing in other markets. DESTINY-Breast05 had previously been granted Priority Review and Breakthrough Therapy Designation by the FDA.

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Related Topics and Keywords

AstraZeneca, breast cancer, enhertu, HER2, HER2-positive early breast cancer