Trastuzumab Deruxtecan (Enhertu) Plus Pertuzumab Approved in EU for 1st-Line HER2-Positive Breast Cancer

AstraZeneca and Daiichi Sankyo's trastuzumab deruxtecan (Enhertu), in combination with pertuzumab, has been approved in the European Union (EU) for 1st-line treatment of adults with unresectable or metastatic HER2-positive breast cancer, the companies announced September 1, 2026.¹ The approval marks the first new 1st-line regimen for this indication in more than a decade and is based on the phase 3 DESTINY-Breast09 trial, in which the combination reduced the risk of disease progression or death by 44% compared with a taxane, trastuzumab, and pertuzumab (THP) regimen, with median progression-free survival (PFS) exceeding 3 years.¹

"For patients diagnosed with HER2-positive metastatic breast cancer, maintaining disease control for as long as possible in the 1st-line setting is a critical treatment goal," said Cristina Saura, MD, PhD, steering committee member of Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology in Barcelona, and investigator for the DESTINY-Breast09 trial, in a company press release.¹ "The combination of trastuzumab deruxtecan and pertuzumab represents a significant therapeutic advance, with progression-free survival exceeding three years compared to approximately two years with the current standard of care, and has the potential to become the new first-line standard of care."

What did the DESTINY-Breast09 trial show?

DESTINY-Breast09 is a global, multicenter, randomized, open-label phase 3 trial that enrolled 1157 patients with HER2-positive metastatic breast cancer who had not previously received chemotherapy or HER2-targeted therapy for metastatic disease, randomized 1:1:1 to trastuzumab deruxtecan plus pertuzumab, trastuzumab deruxtecan plus placebo, or THP. In the combination arm compared with THP, median PFS was 40.7 months versus 26.9 months, a 44% reduction in the risk of disease progression or death (hazard ratio, 0.56; 95% confidence interval, 0.44-0.71; p<0.00001), as assessed by blinded independent central review.¹

The confirmed objective response rate was 85.1% with the combination versus 78.6% with THP, and complete responses occurred in 15.1% versus 8.5% of patients, respectively.² Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 54.9% of patients receiving the combination versus 52.4% with THP, with the most common including neutropenia, hypokalemia, and anemia. The overall safety profile was consistent with each individual therapy's known profile, with no new safety concerns identified.¹^,²

Why is a new 1st-line regimen significant for HER2-positive breast cancer?

"HER2-positive metastatic breast cancer is an aggressive disease, so to give patients the best chance of improving long-term outcomes, it is critical to initiate effective HER2-directed therapy early and continue treatment for as long as patients benefit," said Dave Fredrickson, executive vice president of the oncology hematology business unit at AstraZeneca, in the release.¹

HER2-positive disease affects an estimated 15% to 20% of patients with metastatic breast cancer, and while HER2-targeted therapies have improved outcomes, most patients experience disease progression within 2 years of 1st-line THP, which has served as the standard of care for more than a decade.¹ Only about 30% of patients with metastatic breast cancer are expected to survive 5 years following diagnosis.¹ Based on these results, the combination regimen has been included in the ESMO Clinical Practice Guidelines as a category IA 1st-line treatment option for metastatic HER2-positive breast cancer, regardless of hormone receptor status.³

What's next for the Enhertu-pertuzumab combination?

The combination is already approved as a 1st-line treatment for unresectable or metastatic HER2-positive breast cancer in more than 40 countries worldwide.¹ Trastuzumab deruxtecan is also under EU review for patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant HER2-targeted treatment, based on data from the DESTINY-Breast05 trial. Following this EU approval, AstraZeneca owes Daiichi Sankyo a $100 million milestone payment for the indication, under the companies' 2019 collaboration agreement.¹

What are the limitations?

This analysis is from a prespecified interim analysis, and the trastuzumab deruxtecan monotherapy arm of the trial remains blinded pending final PFS analysis. How the combination regimen compares with trastuzumab deruxtecan alone is not yet known. The modestly higher overall grade 3 or higher adverse event rate in the combination arm should be weighed against its PFS benefit.

References

1. AstraZeneca. Enhertu plus pertuzumab approved in the EU as first new regimen in more than a decade for the 1st-line treatment of patients with HER2-positive metastatic breast cancer. Press release. Published September 1, 2026. Accessed September 1, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/enhertu-approved-in-eu-for-1l-her2-positive-mbc.html
2. Tolaney SM, Jiang Z, Zhang Q, et al; DESTINY-Breast09 Trial Investigators. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2026;394(6):551-562. doi:10.1056/NEJMoa2508668
3. de Azambuja E, Barrios C, Bartsch R, et al. Metastatic breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2026;37(9):1203-1219. doi:10.1016/j.annonc.2026.05.707