FDA Grants Breakthrough Therapy Designation to T-DXd Early HER2+ BC

The FDA has granted breakthrough therapy designation (BTD) to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant systemic therapy and remain at high risk of recurrence.¹

This regulatory milestone is based on data from the phase 3 DESTINY-Breast05 trial (NCT04622319).² The study demonstrated that T-DXd significantly improved invasive disease-free survival (IDFS) compared with the current standard of care, trastuzumab emtansine (T-DM1; Kadcyla). The trial results were recently presented at a presidential symposium during the 2025 European Society for Medical Oncology (ESMO) Congress and published in The New England Journal of Medicine.³

Addressing Residual Disease

In the neoadjuvant setting, achieving a pathologic complete response (pCR)—defined as the absence of residual invasive cancer in the breast or lymph nodes—is a critical prognostic indicator for long-term survival. However, approximately 50% of patients with HER2-positive early breast cancer do not achieve pCR after neoadjuvant treatment, placing them at an elevated risk of disease recurrence.^4,5

While T-DM1 is the established adjuvant therapy for patients with residual disease, clinical data indicate that roughly 20% of these patients still experience invasive disease recurrence or death within 5 years. Furthermore, T-DM1 has shown limited efficacy in reducing the risk of central nervous system recurrence, a significant concern in HER2-positive disease.⁶

“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,” said Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, in a press release.¹

DESTINY-Breast05 Trial Design and Findings

DESTINY-Breast05 is a global, multicenter, randomized, open-label phase 3 trial that enrolled 1635 patients. Participants were randomized to receive either T-DXd (5.4 mg/kg) or T-DM1. High risk of recurrence was defined as having inoperable cancer prior to neoadjuvant therapy or pathologically positive axillary lymph nodes following treatment.

The primary end point of investigator-assessed IDFS was met, showing a robust clinical benefit for T-DXd over T-DM1. Secondary end points, including overall survival and brain metastases-free interval, also favored the T-DXd.

This designation marks the tenth BTD granted to T-DXd, reflecting its expanding role across the HER2-positive and HER2-low oncology landscape.

The potential transition of T-DXd into the early breast cancer setting could shift the treatment paradigm for high-risk patients. Clinical guidelines currently emphasize the importance of escalating therapy for those who fail to achieve pCR.

“DESTINY-Breast05 clearly demonstrated that fam-trastuzumab deruxtecan-nxki may help halt invasive disease recurrence over the current standard of care, resulting in potentially more patients achieving a cure,” said Ken Takeshita, global head of Research and Development at Daiichi Sankyo, in a news release.

REFERENCES

1. Enhertu granted Breakthrough Therapy Designation in the US as post-neoadjuvant therapy for patients with HER2-positive early breast cancer. News release. AstraZeneca. December 22, 2025. Accessed December 22, 2025. https://tinyurl.com/2y84hmyw

2. A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated May 9, 2025. Accessed December 22, 2025. https://clinicaltrials.gov/study/NCT04622319

3. Loibl S, Park YH, Shao Z, et al. Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer. N Engl J Med. 2025 Dec 10. doi: 10.1056/NEJMoa2514661. Epub ahead of print. PMID: 41370739.

4. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.

5. Spring LM, et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res. 2020;26(12):2838–2284.

6. Geyer CE Jr, Untch M, Huang CS, et al.Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025 Jan 16;392(3):249-257. doi: 10.1056/NEJMoa2406070. PMID: 39813643.