EU Approves Enhertu for HR-Positive, HER2-Low, HER2-Ultralow Metastatic Breast Cancer Following Endocrine Therapy

The European Commission has approved trastuzumab deruxtecan (T-DXd; brand name Enhertu) as the first HER2-directed therapy for 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 are no longer considered suitable candidates for further endocrine treatment.

The decision was based on results from the phase III DESTINY-Breast06 trial, which demonstrated a significant improvement in progression-free survival (PFS) with T-DXd compared with chemotherapy. Patients treated with T-DXd experienced a median PFS of 13.2 months versus 8.1 months with chemotherapy in both the HER2-low and HER2-ultralow populations (hazard ratio [HR], 0.64; 95% CI: 0.54-0.76; P<0.0001). In the subgroup of patients with chemotherapy-naive, HR-positive, HER2-low disease, T-DXd showed a 38% reduction in the risk of disease progression or death (HR, 0.62; CI: 0.52-0.75; P<0.0001).

“This approval introduces a new treatment option for HR-positive metastatic breast cancers that express HER2,” said Dr. Giuseppe Curigliano, professor of medical oncology at the University of Milan and principal investigator of the DESTINY-Breast06 trial. “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.”

The trial enrolled patients with HER2-low and HER2-ultralow disease, a classification determined by central laboratory HER2 testing. Approximately 85% to 90% of patients screened for HR-positive, HER2-negative metastatic breast cancer were found to have HER2-low or HER2-ultralow expression, emphasizing the clinical relevance of precise HER2 testing even at low expression levels.

Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit, underscored the significance of this diagnostic shift: “This approval underscores the importance of testing metastatic breast cancer tumours for any IHC [immunohistochemistry] 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.”

Trastuzumab deruxtecan, an antibody-drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo, was previously approved in the European Union based on DESTINY-Breast04 data for patients who had received prior chemotherapy. The latest approval extends its use to earlier treatment lines and to a broader population—including those with HER2-ultralow expression—for whom chemotherapy was previously the only option after endocrine resistance developed.

According to Ken Keller, global head of oncology business and CEO at Daiichi Sankyo, “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.”

Trastuzumab deruxtecan’s safety profile in DESTINY-Breast06 was consistent with prior studies, with no new safety concerns reported.

The drug was approved earlier this year in the US for this indication, and regulatory submissions are ongoing in Japan and other countries.