FDA Grants Breakthrough Status to Enhertu for Some HER2+ Early Breast Cancers

The U.S. Food and Drug Administration has granted breakthrough therapy designation to Enhertu (fam-trastuzumab deruxtecan-nxki) for adult patients with HER2-positive early breast cancer with residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant treatment, and who are at high risk of disease recurrence, according to a news release from AstraZeneca.

AstraZeneca and Daiichi Sankyo’s Enhertu's breakthrough therapy designation as a post-neoadjuvant treatment option for patients with HER2-positive early breast cancer marks the tenth of its kind, with the newest regulatory decision supported by findings from the phase 3 DESTINY-Breast05 trial.

DESTINY-Breast05 represents the second positive Enhertu study in early breast cancer reported in 2025. DESTINY-Breast11 was the first, and it assessed patients with high-risk HER2-positive disease in the neoadjuvant setting and is currently undergoing FDA review.

DESTINY-Breast05 results were shared during a Presidential Symposium at the 2025 European Society for Medical Oncology (ESMO) Congress and later published in The New England Journal of Medicine.

“For patients with residual disease after neoadjuvant treatment, the post-neoadjuvant setting represents a critical opportunity to reduce the risk of recurrence and prevent progression to metastatic disease. This breakthrough therapy designation highlights the impressive clinical benefit of Enhertu over the current standard of care and underscores its potential to become an important treatment option in the post-neoadjuvant setting,” Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, said in the news release.

A breakthrough therapy designation from the FDA is granted to potential new medicines and treatment combinations that are meant to treat a serious condition and address a significant unmet medical need, in turn, accelerating the development and regulatory review process.

DESTINY-Breast05 Trial Design and Goals

DESTINY-Breast05 is a global, multicenter, randomized study designed to compare the safety and effectiveness of Enhertu, given at 5.4 milligrams per kilogram (mg/kg), with trastuzumab emtansine (T-DM1) for HER2-positive early breast cancer patients with residual invasive cancer in the breast or lymph nodes under the arm (axillary lymph nodes) after receiving neoadjuvant therapy; these patients also faced a high risk of the disease returning. High risk of recurrence was defined as having cancer that was inoperable before neoadjuvant treatment, or having axillary lymph nodes that remained cancer positive following neoadjuvant therapy.

The primary end point of DESTINY-Breast05 is investigator-assessed invasive disease-free survival. Invasive disease-free survival is the time from randomization until the first invasive recurrence in the breast, axillary lymph nodes, or a distant site, or death from any cause. A key secondary end point is investigator-assessed disease-free survival. Additional secondary measures include overall survival, distant recurrence-free interval, brain metastases-free interval, and safety findings.

DESTINY-Breast05 enrolled 1,635 patients across Asia, Europe, North America, Oceania, and South America.

Safety Information and Important Risks with Enhertu

The news release strongly emphasized the risk of interstitial lung disease and pneumonitis, including fatal cases, and embryo-fetal toxicity with Enhertu.

It is important to monitor for interstitial lung disease and promptly investigate symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. In all patients with grade 2 or higher interstitial lung disease/pneumonitis, it is advised to permanently discontinue Enhertu. Patients should be informed of these risks and urged to report symptoms immediately.

Moreover, exposure to Enhertu during pregnancy can cause serious harm to an unborn baby. Patients must be advised of this risk and the need for effective birth control.

More Information on Enhertu and Its Potential

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “This tenth breakthrough therapy designation reinforces how Enhertu continues to deliver transformational results that advance the treatment of breast cancer. We look forward to working with the FDA with the goal of bringing Enhertu to the post-neoadjuvant setting of HER2-positive early breast cancer, as DESTINY-Breast05 clearly demonstrated that Enhertu may help halt invasive disease recurrence over the current standard of care, resulting in potentially more patients achieving a cure.”

Enhertu is a targeted HER2-directed DXd antibody drug conjugate, consisting of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers.

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