Key Points:
- Enhertu Perjeta approval: FDA clears the combination as first-line therapy for HER2-positive metastatic breast cancer, replacing the long-standing THP regimen.
- DESTINY-Breast09 trial: combination reduces progression/death risk by 44%; median progression-free survival 40.7 months vs 26.9 months with THP.
- Safety: generally consistent, but 12% of patients experienced lung toxicity (ILD); monitoring required.
The Food and Drug Administration approves AstraZeneca and Daiichi Sankyo’s Enhertu combined with Roche’s Perjeta as a first-line treatment for unresectable or metastatic HER2-positive breast cancer. The Enhertu Perjeta approval expands the use of the antibody-drug conjugate based on phase three trial results.
The Enhertu Perjeta approval allows the Enhertu-Perjeta regimen for patients whose disease tests positive for HER2 using an FDA-approved diagnostic. The approval moves Enhertu into the earliest treatment setting for advanced disease, reshaping a space long dominated by Roche’s THP regimen of Perjeta, Herceptin, and chemotherapy.
Enhertu, developed by Daiichi Sankyo and AstraZeneca, first won FDA approval in 2019 as a third-line option for HER2-positive metastatic breast cancer. Regulators expanded its use to second-line therapy in 2022. Perjeta, a monoclonal antibody from Roche, was approved in 2012 as part of first-line therapy and has remained a standard of care for more than a decade.
Approval Shifts Longstanding Standard of Care
The Enhertu Perjeta approval follows interim results from the Destiny-Breast09 phase three trial, which compared the Enhertu-Perjeta combination with the THP regimen in patients who had not received prior treatment for metastatic disease.
Investigators found that the new combination reduced the risk of disease progression or death by 44% compared with THP. Median progression-free survival reached 40.7 months for patients receiving Enhertu and Perjeta, versus 26.9 months for those treated with THP.
“With a median progression-free survival exceeding three years, versus approximately two years with THP, this regimen should become a new first-line standard of care in this setting,” said Dr. Sara Tolaney of the Dana-Farber Cancer Institute, the trial’s principal investigator, in a statement.
The progression-free survival benefit was consistent across prespecified patient subgroups, according to the companies.
Phase Three Trial Shows Strong Survival Gains
AstraZeneca said the Enhertu Perjeta approval reflects a broader strategy to move Enhertu earlier in treatment, where clinical gains may have a greater effect on long-term outcomes.
“With this approval, we are bringing Enhertu to the earliest setting for HER2-positive metastatic breast cancer, where optimizing efficacy has an important impact,” said Dave Fredrickson, head of oncology and hematology at AstraZeneca.
In another arm of Destiny-Breast09, researchers evaluated Enhertu as a single agent against THP. That comparison did not reach statistical significance for progression-free survival at the interim analysis, the companies said.
Enhertu has emerged as a key product for both partners. The drug helped establish the HER2-low category in breast cancer and received FDA approval in January as a second-line therapy for tumors with HER2-low or HER2-ultralow expression.
Safety Profile Holds, Lung Risk Requires Monitoring
The FDA said the safety profile of the Enhertu-Perjeta combination was generally consistent with the known risks of each drug. No new safety signals were identified in the trial.
However, the study showed higher rates of interstitial lung disease, or ILD, a known risk associated with antibody-drug conjugates using Daiichi Sankyo’s DXd platform. Adjudicated drug-related ILD or pneumonitis occurred in 12% of patients treated with Enhertu and Perjeta, compared with 1% in the THP group.
Most ILD cases in the combination arm were mild to moderate, but two deaths were reported, representing 0.5% of treated patients. All ILD events in the THP arm were low grade.
Doctors have become “quite used to managing” the side effect, Tolaney said earlier this year when the data were presented at the American Society of Clinical Oncology meeting in Chicago.
The Enhertu Perjeta approval also has commercial implications. Combined global sales of Enhertu reached $3.75 billion in 2024, up from $2.57 billion a year earlier. Roche reported $3.6 billion in 2024 sales for Perjeta.
