AstraZeneca Plc (LON:AZN) and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has been approved in the European Union (EU) as a monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer who have received at least one endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of treatment.
The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the DESTINY-Breast06 Phase III trial, which were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.
HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.1 Despite being classified as HER2-negative, many of these tumours still have some level of HER2 expression. Currently, regardless of HER2 expression, endocrine-based therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer. Following endocrine-based therapy, some patients discontinue treatment, and others are treated with conventional chemotherapy which is associated with poor response rates and outcomes.2-5
Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and principal investigator for the trial, said: “This approval introduces a new treatment option for HR-positive metastatic breast cancers that express HER2. In DESTINY-Breast06, Enhertu outperformed chemotherapy, providing progression-free survival of more than one year for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer, demonstrating the benefit of treating these patients with Enhertu instead of chemotherapy.”
Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “Enhertu continues to open up new approaches to the diagnosis and treatment of patients with metastatic breast cancer. This approval underscores the importance of testing metastatic breast cancer tumours for any IHC staining to identify patients with HR-positive, HER2-low or HER2-ultralow disease who may be eligible for Enhertu once sustained responses are no longer achieved with endocrine-based therapy.”
Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, said: “Enhertu continues to evolve what is possible with breast cancer treatment, becoming the first HER2-directed medicine approved in the EU for patients with HR-positive metastatic breast cancer with HER2-low or HER2-ultralow expression following endocrine therapy. Today’s approval expands the use of Enhertu to now include an earlier treatment setting of HER2-low metastatic breast cancer and broadens the patient population eligible for treatment to those with HER2-ultralow disease.”
In the trial, Enhertu showed a 38% reduction in the risk of disease progression or death versus chemotherapy (hazard ratio [HR] 0.62; confidence interval [CI]: 0.52-0.75; p<0.0001) in patients with chemotherapy-naïve HR-positive, HER2-low metastatic breast cancer with a median progression-free survival (PFS) of 13.2 months versus 8.1 months.
In the overall trial population (patients with HER2-low or HER2-ultralow metastatic breast cancer), the median PFS was 13.2 months in patients randomised to Enhertu compared to 8.1 months in those randomised to chemotherapy (HR 0.64; 95% CI: 0.54-0.76; p<0.0001). In an exploratory analysis, results were consistent between patients with HER2-low expression and HER2-ultralow expression.
HER2 testing in the trial was conducted by a central laboratory. Approximately 85-90% of patients with HR-positive, HER2-negative metastatic breast cancer screened were determined to be HER2-low or HER2-ultralow.6
The safety profile of Enhertu in DESTINY-Breast06 was consistent with previous clinical trials of Enhertu in breast cancer with no new safety concerns identified.
Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.
Enhertu was approved in the US earlier this year based on the DESTINY-Breast06 results. Regulatory applications are under review in Japan and several other countries for this indication.
Enhertu is already approved in more than 75 countries, including the EU, for patients with HER2-low metastatic breast cancer who have received prior chemotherapy 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.
References
- National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed April 2025.
- Manohar P, et al. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med. 2022 Feb 12; 19(2): 2020-212
- Cortes J, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914-923.
- Yuan P, et al. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019;112:57-65.
- Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer. JAMA Oncol. 2018;4(10):1367-1374.
- Salgado RF, et al. LBA21 – Human epidermal growth factor receptor 2 (HER2)-low and HER2-ultralow status determination in tumors of patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06). Annals of Oncology. (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.
