Enhertu^® (trastuzumab deruxtecan) in combination with pertuzumab has been recommended for approval in the European Union (EU) for the first-line treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization [ISH]+) breast cancer.

Enhertu is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/NYSE: AZN).

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the DESTINY-Breast09 phase 3 trial presented at the 2025 American Society of Clinical Oncology Annual Meeting and subsequently published in The New England Journal of Medicine. The recommendation will now be reviewed by the European Commission, which has the authority to grant marketing authorizations for medicines in the EU.

In DESTINY-Breast09, Enhertu in combination with pertuzumab reduced the risk of disease progression or death by 44% versus a taxane, trastuzumab and pertuzumab (THP) (hazard ratio: 0.56; 95% confidence interval [CI]: 0.44-0.71; p<0.00001) in patients (n=383) with HER2 positive metastatic breast cancer who had not received prior chemotherapy or HER2 targeted therapy or had received neoadjuvant or adjuvant HER2 targeted therapy more than six months before the diagnosis of advanced or metastatic disease. Median progression-free survival (PFS) was 40.7 months (95% CI: 36.5-not estimable [NE]) with Enhertu in combination with pertuzumab compared to 26.9 months (95% CI: 21.8-NE) with THP as assessed by blinded independent central review (BICR). The PFS benefit was consistent across subgroups, including the prespecified stratification factors of hormone receptor (HR) status, de novo or recurrent disease and PIK3CA mutation status.

Confirmed objective response rate (ORR) was 85.1% (95% CI: 81.2-88.5) for Enhertu in combination with pertuzumab compared to 78.6% (95% CI: 74.1-82.5) with THP. There were 58 (15.1%) complete responses (CR) and 268 (70.0%) partial responses (PR) with Enhertu plus pertuzumab compared to 33 (8.5%) CRs and 271 (70.0%) PRs with THP. Median duration of response (DOR) for Enhertu plus pertuzumab exceeded three years (39.2 months) versus 26.4 months for THP.

“Enhertu in combination with pertuzumab improved progression-free survival by more than one year compared with the current first-line standard of care, representing a meaningful advantage early in the treatment of patients with metastatic HER2 positive disease,” said John Tsai, MD, Global Head, R&D, Daiichi Sankyo. “Today’s positive CHMP opinion brings us closer to making Enhertu available in the EU as a first-line treatment option for eligible patients with HER2 positive metastatic breast cancer, marking an important milestone in moving this medicine earlier in the treatment pathway.”

“HER2 positive metastatic breast cancer is an aggressive subtype, so starting patients on an effective HER2 targeted treatment early and continuing it for as long as they benefit can have a meaningful impact on long-term outcomes,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. “DESTINY-Breast09 sets a new benchmark with a median progression-free survival of more than three years, underscoring the potential of Enhertu plus pertuzumab to redefine first-line treatment for patients with HER2 positive metastatic breast cancer.”

The safety profile of Enhertu in combination with pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual treatment with no new safety concerns identified. The most common grade 3 or higher treatment-related adverse events that occurred in patients treated with Enhertu in combination with pertuzumab (n=381) were neutropenia (23.9%), hypokalemia (10.2%), and anemia (8.4%). Interstitial lung disease (ILD) or pneumonitis occurred in 12.1% of patients treated with Enhertu in combination with pertuzumab as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 [n=17; 4.5% or grade 2 [n=27; 7.1%]). There were two grade 5 events (0.5%) of ILD or pneumonitis in the Enhertu plus pertuzumab arm.

Enhertu (5.4 mg/kg) in combination with pertuzumab is approved in India, Israel, Saudi Arabia, Singapore, South Korea, Switzerland, the United Arab Emirates and the U.S. as a first-line treatment for adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer, as determined by a locally or regionally approved test, based on the results from the DESTINY-Breast09 trial.

Enhertu is also under review in the EU 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.