FDA May 2026

Enhertu in Early HER2-Positive Breast Cancer. What Did DESTINY-Breast11 and DESTINY-Breast05 Change?

Q: Is Enhertu suitable for all patients with HER2-positive early breast cancer?

No. The new FDA indications apply to specific situations: stage II–III HER2-positive breast cancer before surgery, and residual invasive disease after neoadjuvant HER2-directed therapy. For small low-risk tumors the strategy may differ.

Q: Is this already a new standard of care?

In the US, the FDA approved two new indications. For other countries, including Russia, you need to check separately the registered indications, clinical guidelines, drug availability and the possibility of prescribing it. The data are very important medically, but they have to be applied in the specific clinical context.

Q: What does residual invasive disease mean?

It is the situation when, after preoperative therapy and surgery, viable invasive tumor cells remain in the resected breast tissue or lymph nodes. This is an important risk factor for recurrence and a reason to discuss more intensive postoperative therapy.

Q: Why is HER2 status important?

Enhertu is a HER2-directed antibody-drug conjugate. The new FDA indications apply to HER2-positive breast cancer (IHC 3+ or FISH+). Therefore the quality and accuracy of HER2 determination are critically important. In ambiguous cases the material sometimes needs to be reviewed or testing repeated.

Q: Is Enhertu available in Russia?

Enhertu (trastuzumab deruxtecan) is registered in Russia. But registration does not mean that all foreign indications automatically apply. At the time of writing, the Russian indications differ from the new FDA indications in early HER2-positive breast cancer.

On May 15, 2026, the FDA approved Enhertu (trastuzumab deruxtecan, fam-trastuzumab deruxtecan-nxki, T-DXd) for two new indications in early HER2-positive breast cancer.

The first indication applies to treatment before surgery: Enhertu followed by a taxane, trastuzumab and pertuzumab for adult patients with stage II–III HER2-positive breast cancer.

The second indication applies to treatment after surgery: Enhertu for patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant HER2-directed therapy.

So Enhertu is moving from the setting of advanced and metastatic breast cancer into treatment with potentially curative intent, aimed at reducing the risk of recurrence in patients with early HER2-positive disease — especially those whose tumor is high-risk to begin with or has not fully responded to preoperative therapy.

At the moment this is an approval by the US regulator. It is based on two phase III trials: DESTINY-Breast11 for the neoadjuvant setting, and DESTINY-Breast05 for the adjuvant setting in residual invasive disease after preoperative therapy. In Russia, Enhertu (trastuzumab deruxtecan) is registered, but the Russian indications at the time of writing apply primarily to unresectable or metastatic HER2-positive and HER2-low breast cancer, as well as certain other tumors — but not to the new FDA early breast cancer indications.

What happened in brief

The FDA approved Enhertu for the neoadjuvant treatment of stage II–III HER2-positive breast cancer. First Enhertu, then the taxane + trastuzumab + pertuzumab block.
The FDA also approved Enhertu for the adjuvant treatment of HER2-positive breast cancer if residual invasive disease remains after neoadjuvant therapy with trastuzumab and a taxane.
In DESTINY-Breast11, the pathologic complete response rate was higher with Enhertu followed by THP than with ddAC followed by THP (67.3% vs. 56.3%; p=0.003).
In DESTINY-Breast05, Enhertu reduced the risk of invasive recurrence or death versus T-DM1 by 53% (HR 0.47; 95% CI 0.34–0.66; p<0.0001).

Key numbers from the studies

DESTINY-Breast11 — treatment before surgery

phase III trial;
927 patients with high-risk HER2-positive early breast cancer;
comparison: Enhertu for 4 cycles followed by 4 cycles of taxane, trastuzumab and pertuzumab versus dose-dense doxorubicin+cyclophosphamide followed by taxane, trastuzumab and pertuzumab;
primary endpoint — pathologic complete response (pCR), i.e. no invasive tumor in the breast and axillary lymph nodes after preoperative therapy;
pCR: 67.3% vs. 56.3%;
absolute pCR difference: 11.2% (p=0.003);
at the time of the pCR analysis EFS events were few — 29 events (4.5%), OS events — 12 (1.9%);
the FDA noted that EFS and OS in DESTINY-Breast11 were not statistically controlled or sufficiently powered secondary endpoints.

DESTINY-Breast05 — treatment after surgery in residual disease

phase III trial;
1,635 patients with HER2-positive breast cancer and residual invasive disease after neoadjuvant HER2-directed therapy;
comparison: Enhertu vs. T-DM1;
treatment: up to 14 cycles or until disease recurrence or unacceptable toxicity;
primary endpoint: invasive disease-free survival (iDFS);
reduction in the risk of invasive recurrence or death: 53% (p<0.0001);
3-year iDFS: 92.4% in the Enhertu arm vs. 83.7% in the T-DM1 arm.

On the safety side, the Enhertu followed by THP regimen had a comparable rate of drug-related adverse events and interstitial lung disease/pneumonitis compared to ddAC-THP, as well as lower rates of grade 3+ adverse events, serious adverse events, treatment discontinuations, left ventricular dysfunction and hematologic toxicity. At the same time, the risk of interstitial lung disease/pneumonitis remains a fundamentally important issue with Enhertu — it requires active monitoring and timely treatment interruption or modification when suspicious symptoms appear.

Why this matters in practice

HER2-positive early breast cancer today is often treated in several stages. If the tumor is large enough, lymph nodes are involved, or other high-risk features are present, treatment frequently begins before surgery. This allows tumor shrinkage, assessment of sensitivity to therapy, and a decision about whether postoperative escalation is needed based on the surgical pathology.

Until now, one of the key reference points after neoadjuvant therapy was the fact of residual invasive tumor. If the tumor disappeared completely on pathology after preoperative therapy, the prognosis is usually better. If residual disease remains, the risk of recurrence is higher and a more intensive postoperative strategy is needed. This is exactly the situation in which DESTINY-Breast05 is especially practically important.

The second important part of the news concerns neoadjuvant treatment. DESTINY-Breast11 shows that Enhertu can increase the pathologic complete response rate compared to the anthracycline-containing ddAC-THP regimen. This is important as a possible step toward changing preoperative regimens in patients with high-risk HER2-positive early breast cancer.

In practice, this reinforces the importance of careful treatment planning before the first infusion. In HER2-positive early breast cancer it is important to discuss in advance whether neoadjuvant therapy is needed, which regimen to choose, how to assess the response, what to do in case of residual disease after surgery, whether radiotherapy is needed, and how to take the hormone receptor status and recurrence risk into account.

Commentary by Evgeny Ledin

This news is a long-awaited result in oncology. The first group is patients with stage II–III HER2-positive breast cancer who are choosing preoperative therapy. The second is patients who, after neoadjuvant treatment and surgery, still have residual invasive disease. It is in the second situation that the question "what to do next" is especially important, because after surgery there is a window in which we can try to reduce the risk of recurrence.

What does this change in treatment choice? In my view, these data further emphasize that in early HER2-positive breast cancer surgery, chemotherapy, anti-HER2 therapy and radiation cannot be considered separately. The strategy has to be built as a route: what we do before surgery, how we assess the response, and what we change after surgery if pathologic complete response is not achieved.

I see these data as a very important step. Enhertu has already changed the treatment of metastatic HER2-positive breast cancer, and now it is entering earlier stages, where the cost of a mistake is higher because we are talking about a potentially curable situation. The decision to use innovative therapy must be made with maximum care — with accurate HER2 determination, assessment of stage, recurrence risk, lung status, and understanding of which indications actually apply in a given country.

For some patients with early HER2-positive breast cancer these new data may change the treatment route. And there is now an additional reason to seek a competent second opinion before starting treatment or right after surgery — especially if there is residual disease and the postoperative strategy has to be chosen.

Get a second opinion

When a second opinion is especially useful

HER2-positive stage II–III breast cancer has been diagnosed recently and preoperative therapy is still being chosen;
neoadjuvant therapy has already been given and residual invasive disease is found after surgery;
it is not clear which preoperative regimen is better — anthracycline-containing, anthracycline-free, or an ADC-based one;
there are doubts about HER2 status (discordant IHC and FISH results, borderline interpretation);
the patient wants to understand whether the DESTINY-Breast11 and DESTINY-Breast05 data apply to their specific situation.

What to prepare for the consultation

histopathology report;
HER2 IHC and FISH results, if performed;
ER, PR, Ki-67 data;
discharge summaries for treatment already received;
surgical protocol and postoperative pathology report;
CT, MRI, PET-CT, ultrasound, mammography or breast MRI results;
data on lymph node status before and after treatment;
blood test results;
information about comorbidities, especially lung and heart disease;
list of medications the patient takes regularly.

Sources:

Frequently Asked Questions

Is Enhertu suitable for all patients with HER2-positive early breast cancer?