AstraZeneca and Daiichi Sankyo’s Enhertu-based regimen shows 44% risk reduction and over three-year PFS in HER2-positive metastatic breast cancer

(IN BRIEF) AstraZeneca and Daiichi Sankyo’s supplemental Biologics License Application for Enhertu plus pertuzumab has been accepted for Priority Review by the FDA for the first-line treatment of HER2-positive metastatic breast cancer. The application is supported by data from the Phase III DESTINY-Breast09 trial, which showed the combination cut the risk of disease progression or death by 44% compared to THP and achieved a median progression-free survival of over 40 months. The FDA’s decision date is expected in early 2026, with the therapy also benefiting from Breakthrough Therapy Designation and Real-Time Oncology Review. With high response rates and durable outcomes, Enhertu plus pertuzumab has the potential to replace THP as the standard of care in the first-line setting for this aggressive breast cancer subtype.

(PRESS RELEASE) CAMBRIDGE, 24-Sep-2025 — /EuropaWire/ — AstraZeneca and Daiichi Sankyo have announced that the US Food and Drug Administration (FDA) has accepted and granted Priority Review for a supplemental Biologics License Application (sBLA) for Enhertu® (trastuzumab deruxtecan) in combination with pertuzumab as a first-line treatment for adults with unresectable or metastatic HER2-positive breast cancer.

The FDA’s decision is based on the positive results of the DESTINY-Breast09 Phase III trial, which demonstrated that Enhertu plus pertuzumab reduced the risk of disease progression or death by 44% compared with the current standard regimen of a taxane, trastuzumab, and pertuzumab (THP). Median progression-free survival (PFS) reached 40.7 months in the Enhertu arm, versus 26.9 months with THP—marking the first significant advancement in this setting in more than a decade.

Priority Review status shortens the FDA’s review timeline for applications that, if approved, could substantially improve current treatment approaches. A regulatory decision is expected in the first quarter of 2026. In addition, the FDA recently granted Breakthrough Therapy Designation (BTD) to Enhertu in this indication, further expediting its development and review. The application is also being evaluated under the Real-Time Oncology Review (RTOR) program, which allows portions of the submission to be reviewed before the full application is filed.

“The DESTINY-Breast09 trial set a new benchmark, with Enhertu plus pertuzumab producing a median PFS of more than three years and nearly doubling the number of patients showing no detectable disease,” said Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca. “For patients in the first-line metastatic setting, where up to one third may not receive a second-line therapy, such durable responses are especially meaningful.”

Ken Takeshita, Global Head of R&D at Daiichi Sankyo, added: “These data show Enhertu plus pertuzumab delayed progression beyond three years compared to two years with the current standard. Priority Review brings us closer to making this combination available as a potential new standard of care in the 1st-line HER2-positive metastatic setting.”

Trial results support potential shift in standard of care
DESTINY-Breast09 enrolled 1,157 patients globally. Enhertu plus pertuzumab achieved an objective response rate (ORR) of 85.1% compared to 78.6% with THP, including 58 complete responses versus 33. The safety profile was consistent with the known tolerability of each therapy, with no new safety concerns observed.

HER2-positive metastatic breast cancer is a particularly aggressive form of the disease, representing 15–20% of breast cancers and affecting roughly 10,000 patients each year in the first-line metastatic setting in the US. While HER2-targeted regimens have improved outcomes, most patients still progress within two years of treatment with THP. Enhertu plus pertuzumab, if approved, could extend this timeline substantially and establish a new benchmark in care.

Enhertu and ongoing development
Enhertu is a specifically engineered HER2-directed DXd antibody-drug conjugate (ADC) developed by Daiichi Sankyo and jointly commercialised with AstraZeneca. It is already approved in more than 85 countries for second-line HER2-positive breast cancer, based on results from the DESTINY-Breast03 trial, and has approvals across multiple other HER2-driven cancers. Its broad clinical development programme continues to evaluate the ADC as monotherapy and in combinations across solid tumours.

Notes

HER2-positive metastatic breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.⁴ More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally.⁴ In the US, more than 300,000 cases of breast cancer are diagnosed annually with more than 42,000 deaths.⁵ While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.⁶

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast cancer.^7,8 HER2 protein overexpression may occur as a result of HER2 gene amplification.⁹Approximately one in five cases of breast cancer are considered HER2-positive.¹

While HER2-targeted therapies have improved outcomes, prognosis remains poor with most patients experiencing disease progression within two years of 1st-line treatment with THP, which has been the standard of care for more than a decade.^9-12Further, approximately 25-30% of patients do not go on to receive treatment following 1st-line therapy due to discontinuation or death.^13-15

DESTINY-Breast09
DESTINY-Breast09 is a global, multicentre, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) either alone or in combination with pertuzumab versus standard of care THP (a taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab) as a 1st-line treatment in patients with HER2-positive metastatic breast cancer.

Patients were randomised 1:1:1 to receive either Enhertu monotherapy with a pertuzumab matching placebo; Enhertu in combination with pertuzumab; or THP. Randomisation was stratified by prior treatment (de novo metastatic disease versus progression from early-stage disease), hormone receptor status and PIK3CA mutation status.

The primary endpoint of DESTINY-Breast09 is PFS as assessed by blinded independent central review in both the Enhertu monotherapy and Enhertu combination arms. Secondary endpoints include investigator-assessed PFS, overall survival, ORR, duration of response, pharmacokinetics and safety. The investigational arm assessing Enhertu monotherapy versus THP remains blinded to patients and investigators and will continue to the final PFS analysis.

DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa, Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 85 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridisation [ISH]+) breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 85 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.

Enhertu (5.4mg/kg) is approved in more than 60 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 70 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

Enhertu (5.4 mg/kg) is approved in more than 10 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu clinical development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu as a monotherapy, in combination or sequentially with other cancer medicines across multiple HER2-targetable cancers.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019 and Datroway (datopotamab deruxtecan) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is challenging, and redefining, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.

With Enhertu, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive, HER2-low and HER2-ultralow metastatic breast cancer, and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and aims to reshape the HR-positive space with first-in-class AKT inhibitor, Truqap (capivasertib), the TROP-2-directed ADC, Datroway, and next-generation oral SERD and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in these settings. AstraZeneca is also exploring the potential of saruparib, a potent and selective inhibitor of PARP1, in combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced breast cancer.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to evaluate the potential of Datroway alone and in combination with immunotherapy Imfinzi (durvalumab).

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.

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