Enhertu Plus Pertuzumab Approved for First-Line HER2+ Metastatic Breast Cancer
Enhertu combined with pertuzumab received FDA approval for first-line treatment of HER2-positive metastatic breast cancer, marking the first new treatment in a decade. Real-world data show trastuzumab deruxtecan efficacy is consistent across patient subgroups.
Enhertu (trastuzumab deruxtecan) in combination with pertuzumab has been approved in the US for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer, as determined by a Food and Drug Administration (FDA)-approved test. The approval, announced December 15, 2025, marks the first new treatment in more than a decade for this patient population.
The approval follows Priority Review and Breakthrough Therapy Designation by the FDA and is based on results of the DESTINY-Breast09 Phase III trial. Data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.
In the trial, Enhertu in combination with pertuzumab reduced the risk of disease progression or death by 44% versus a taxane, trastuzumab and pertuzumab (THP) (based on a hazard ratio of 0.56; 95% confidence interval [CI] 0.44-0.71; p<0.0001) as a first-line treatment for patients with HER2-positive metastatic breast cancer. Median progression-free survival (PFS) was 40.7 months with Enhertu plus pertuzumab compared to 26.9 months for THP. The PFS benefit for Enhertu plus pertuzumab versus THP was consistent across subgroups.
The safety profile of Enhertu plus pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual therapy with no new safety concerns identified. This application was approved under the FDA's Real-Time Oncology Review (RTOR), an initiative by the FDA to ensure safe and effective treatments are available to patients as early as possible.
The US regulatory submission was also reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners. As part of Project Orbis, the Enhertu plus pertuzumab first-line regimen is under review by Switzerland's Swissmedic (SMC) and Singapore's Health Sciences Authority (HSA). Separate regulatory applications are also under review in other countries.
Following this approval in the US, an amount of $150 million is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the first-line unresectable or metastatic HER2-positive breast cancer indication. Sales of Enhertu in the US are recognised by Daiichi Sankyo.
Separately, a retrospective, real-world study evaluated outcomes for patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan (T-DXd) across 12 Italian referral hospitals. The DE-REAL study examined outcomes for patients based on numerous clinical features of age, body mass index (BMI), toxicity grading, drug-drug interactions (DDIs), and others. Outcomes of interest included real-world progression-free survival (rwPFS) and overall survival (OS).
A total of 143 patients were included in the study; they were median ages 66 years (range, 37 to 90 years) overall and 57 years at the start of T-DXd therapy. Four patients (3%) were male and 139 were female, 64 of whom had postmenopausal status. Estrogen receptor-positivity was present in 75% of patients.
At a median follow-up time of 12 months, age did not appear to be significantly associated with median rwPFS, which were 10 months for patients younger than 75 years and 9 months for patients 75 years and older (hazard ratio [HR], 1.37; P =.47). Median rwPFS times were 10 months for patients younger than 65 years and 8 months for patients 65 years and older (HR 1.41; P =.22).
However, in patients younger than 65 years, the median OS was 12 months, which was favorable in comparison to the median OS of 10 months in patients 65 years and older (HR, 2.06; P =.02). Comorbidity and polypharmacy rates were higher in patients 65 years and older compared to those younger than 65 (48.6% vs 18.9%; P =.001).
Patients with a BMI of 25 kg/m2 and higher had a median rwPFS of 11 months, which was significantly longer than the median rwPFS of 9 months for patients with a BMI less than 25 kg/m2 (HR, 0.58; P =.04). However, median OS times did not significantly differ by BMI (12 months vs 11 months, respectively; HR, 0.88; P =.7).
An association was also observed between higher median BMI and the presence of toxicities (P =.01). In particular, nausea appeared more prevalent for patients with a BMI of 25 kg/m2 and higher, compared with a BMI of less than 25 kg/m2 (P =.019).
In general, DDIs at baseline did not appear significantly associated with survival outcomes. However, patients having any-risk DDIs more frequently experienced nausea (P =.018) or asthenia (P =.003) than patients with no-risk DDIs. Overall, among the patients of this study, dose reductions were reported in 26% of patients, with permanent T-DXd discontinuation reported in 3%.
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. More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally. In the US, more than 300,000 cases of breast cancer are diagnosed annually with more than 42,000 deaths.