Enhertu (Trastuzumab Deruxtecan) After Neoadjuvant Therapy and Surgery for HER2-Positive Breast Cancer: DESTINY-Breast05 Results
New data have emerged that could change the treatment of HER2-positive early breast cancer after surgery. In the international randomized phase III DESTINY-Breast05 study, Enhertu (trastuzumab deruxtecan) was compared with the current standard T-DM1 in high-risk patients who had residual invasive disease in the breast or lymph nodes after neoadjuvant therapy. A total of 1,635 patients were enrolled.
This concerns a situation where pre-operative treatment has already been given, surgery has been performed, but pathology shows the tumor has not completely disappeared. It is precisely in these patients that the risk of disease recurrence is higher, making the choice of post-operative therapy particularly important.
Study Results
In the study, Enhertu (trastuzumab deruxtecan) reduced the risk of invasive recurrence or death by 53% compared with T-DM1 (HR 0.47; p<0.001). Three-year invasive disease-free survival was 92.4% versus 83.7%.
The advantage was seen not only for the primary endpoint. For the secondary endpoint of DFS, results were virtually identical (HR 0.47), with three-year DFS of 92.3% versus 83.5%. Additionally, Enhertu (trastuzumab deruxtecan) reduced the risk of distant recurrence by 51%. A favorable signal was also noted for brain metastases, although these data should be interpreted cautiously as an important trend rather than a definitive answer. Overall survival data were still immature at the time of the interim analysis.
Safety
Overall, the rate of severe adverse events was comparable between the two groups, but Enhertu (trastuzumab deruxtecan) carries a well-known risk of interstitial lung disease and pneumonitis. The rate of confirmed drug-related pneumonitis was 9.6% versus 1.6% on T-DM1. Most cases were low-grade, but there were also severe events in the Enhertu group, including two fatal cases. This means that monitoring, timely assessment of respiratory symptoms, and careful follow-up are especially important with this therapy.
Regulatory Status
In the US, the application for Enhertu (trastuzumab deruxtecan) in this post-neoadjuvant setting has been accepted by the FDA and granted Priority Review status. A decision is expected in the third quarter of 2026. Submissions are also under review in other major jurisdictions. This represents a serious bid to change clinical practice.
When to Seek a Second Opinion
A repeat consultation is particularly warranted if:
- after neoadjuvant therapy and surgery, the pathology report describes residual invasive disease
- you are being offered T-DM1 but want to understand whether stronger options are already available
- doctors' opinions differ
- there are concerns about toxicity or pneumonitis risk
- you want to understand how closely your treatment plan aligns with the latest data
What to Prepare Before Your Consultation
For a thorough review, it is best to prepare in advance:
- discharge summary from pre-operative treatment
- operative report
- post-operative pathology report
- HER2 testing results
- CT, MRI, or PET-CT data, if available
- information about tolerability of prior therapy
Conclusion
DESTINY-Breast05 is one of the most important developments in the treatment of HER2-positive early breast cancer in recent times. The study showed that Enhertu (trastuzumab deruxtecan) after surgery in patients with residual invasive disease can significantly improve outcomes compared with T-DM1.
Frequently Asked Questions
What does residual invasive disease after neoadjuvant therapy mean?
It means that after pre-operative treatment and the surgery itself, the pathologist still sees invasive tumor in the breast tissue and/or lymph nodes. This is exactly the group of patients studied in DESTINY-Breast05.
What did the DESTINY-Breast05 study show?
Enhertu (trastuzumab deruxtecan) reduced the risk of invasive recurrence or death by 53% compared with T-DM1. Three-year iDFS was 92.4% versus 83.7%.
Has Enhertu been approved after surgery in this setting?
As of March 2026, the application has been accepted by the FDA and received Priority Review status, with a decision expected in the third quarter of 2026. This is very close to a potential change in the standard of care, but the review process is still ongoing.
Why is there so much discussion about pneumonitis risk?
Because for Enhertu, this is an important known risk. In DESTINY-Breast05, confirmed drug-related pneumonitis was observed in 9.6% of patients versus 1.6% on T-DM1. There were also severe cases in the Enhertu group.
Should I switch from T-DM1 to Enhertu on my own?
No. Such decisions cannot be made independently. A review of morphology, residual disease volume, prior treatment, toxicity risks, and drug availability in your specific country is needed.
More answers on the FAQ page.