FDA Grants Priority Review for Enhertu Plus Pertuzumab in First-Line HER2-Positive Breast Cancer

AstraZeneca and Daiichi Sankyo have announced that their supplemental Biologics License Application (sBLA) for Enhertu (fam-trastuzumab deruxtecan-nxki) plus pertuzumab has been accepted and granted Priority Review by the FDA for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer.¹

DESTINY-Breast09 shows significant survival benefit

The Enhertu-pertuzumab combination’s Priority Review was granted based on positive findings from the Phase III DESTINY-Breast09 clinical trial (NCT04784715), which demonstrated a 44% reduction in the risk of disease progression or death versus a taxane, trastuzumab, and pertuzumab (THP) regimen.

In a press release, Susan Galbraith, executive vice president, oncology hematology R&D, AstraZeneca, said: “The DESTINY-Breast09 trial showed that treating patients with HER2-positive metastatic breast cancer with Enhertu in combination with pertuzumab until progression in the first-line setting produced a new landmark of more than 40 months for progression-free survival and nearly doubled the number of patients with no evidence of disease on imaging. This marks the first major evolution in treatment in this first-line setting in more than a decade—a setting where a strong response is crucial, as up to one third of patients may not receive second-line therapy.”

Trial design and endpoints

The DESTINY-Breast09 study is a global, multicenter, randomized, open-label trial conducted across sites in Africa, Asia, Europe, North America, and South America.

• A total of 1,157 patients were randomized 1:1:1 to receive Enhertu monotherapy, Enhertu plus pertuzumab, or THP.
• The primary endpoint is progression-free survival (PFS).
• Key secondary endpoints include investigator-assessed PFS, overall survival (OS), objective response rate (ORR), duration of response (DoR), investigator-assessed time to second progression or death, patient-reported tolerability, pharmacokinetics, and safety.

In the press release, Ken Takeshita, global head, R&D, Daiichi Sankyo, added: “Enhertu in combination with pertuzumab delayed disease progression for more than three years compared to around two years with current standard of care as a first-line treatment for patients with HER2-positive metastatic breast cancer. Receiving Priority Review moves us closer to offering Enhertu to patients even earlier in the metastatic treatment pathway as a potential new first-line treatment option.”

Interim analysis and clinical outcomes

AstraZeneca and Daiichi Sankyo shared data from DESTINY-Breast09 earlier in June. In addition to the mark of a 44% reduction in the risk of disease progression or death mentioned earlier, a prespecified interim analysis showed:²

• Median PFS was 40.7 months with Enhertu plus pertuzumab compared to 6.9 months with THP.
• The PFS benefit of Enhertu plus pertuzumab was consistent across subgroups, including de novo versus recurrent disease, hormone receptor status, and PIK3CA mutation status.
• The confirmed ORR was 85.1% for Enhertu plus pertuzumab versus 78.6% for THP.
• There were 58 complete responses in the Enhertu plus pertuzumab arm compared with 33 in the THP arm.
• Median DoR was 39.2 months with Enhertu plus pertuzumab and 26.4 months with THP.
• OS data were not yet mature, though interim results suggested an early trend in favor of Enhertu plus pertuzumab.

Ongoing research with Enhertu in breast cancer

In addition to DESTINY-Breast09, Enhertu is being evaluated in the Phase III DESTINY-Breast11 trial (NCT05113251) for the treatment of patients with high-risk, locally advanced HER2-positive early-stage breast cancer. Data released in May showed that Enhertu followed by standard HER2-targeted therapy achieved a significant improvement in pathologic complete response rates compared to current standard-of-care chemotherapy, meeting the study’s primary endpoint.³

• DESTINY-Breast11 enrolled 927 patients who were randomized 1:1:1 into three treatment groups.
• Patients received either eight cycles of Enhertu monotherapy, four cycles of Enhertu followed by four cycles of THP, or four cycles of dose-dense doxorubicin and cyclophosphamide followed by four cycles of THP.
• Secondary endpoints include event-free survival, invasive disease-free survival, OS, and safety.

References

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab granted Priority Review in the US as 1st-line treatment for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. September 24, 2025. Accessed September 25, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-plus-pertuzumab-granted-Priority-Review-in-the-US-as-1st-line-treatment-for-patients-with-HER2-positive-metastatic-breast-cancer.html

2. AstraZeneca and Daiichi Sankyo Share Positive Data From Phase III DESTINY-Breast09 Trial of Enhertu Plus Pertuzumab. Applied Clinical Trials. June 2, 2025. Accessed September 25, 2025. https://www.appliedclinicaltrialsonline.com/view/astrazeneca-daiichi-sankyo-share-positive-data-destiny-breast09-trial-enhertu-pertuzumab

3. DESTINY-Breast11 Trial Shows Enhertu Plus THP Significantly Improves Response Rates in High-Risk HER2-Positive Early Breast Cancer. Applied Clinical Trials. May 7, 2025. Accessed September 25, 2025. https://www.appliedclinicaltrialsonline.com/view/destiny-breast11-enhertu-her2-positive-early-breast-cancer