Enhertu with Pertuzumab as First-Line Treatment for HER2-Positive Metastatic Breast Cancer: What Changed After FDA Approval
There is truly important news for patients with HER2-positive metastatic breast cancer. In December 2025, the FDA approved trastuzumab deruxtecan (Enhertu) in combination with pertuzumab for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer.
The DESTINY-Breast09 Study
The approval was based on the DESTINY-Breast09 study. It enrolled 1,157 patients with HER2-positive advanced or metastatic breast cancer who had not previously received chemotherapy or HER2-directed therapy for metastatic disease. Patients who had received neoadjuvant or adjuvant HER2-directed treatment were eligible if more than 6 months had passed since its completion before the development of advanced disease.
The main result of the study is truly impressive. Median progression-free survival by independent review was 40.7 months with Enhertu plus pertuzumab versus 26.9 months with the previous standard regimen of trastuzumab + pertuzumab + paclitaxel (THP). This corresponds to a 44% reduction in the risk of progression or death (HR 0.56; p<0.0001). The objective response rate was also higher: 87% versus 81%. At the time of analysis, overall survival data were still immature.
Why is this news so important for clinical practice? Until now, the combination of paclitaxel, trastuzumab, and pertuzumab remained the standard of care for first-line treatment of HER2-positive metastatic breast cancer. In the official communication about the study, AstraZeneca specifically emphasized that this is the first study in over a decade to show improved outcomes in a broad population of such patients in the first-line setting. For breast oncology, this is truly a major change.
When to Seek a Second Opinion
A case review is particularly warranted if:
- you have recently been diagnosed with HER2-positive metastatic breast cancer and need to choose a first-line treatment
- you have already received different recommendations from different clinics
- there are doubts about the interpretation of HER2 status
- the disease has returned after adjuvant therapy
- you want to understand how current and evidence-based your proposed treatment plan is
What to Prepare Before Your Consultation
To make the consultation truly useful, it is best to prepare in advance the histopathology report, immunohistochemistry results, discharge summaries from previous treatment, CT, MRI, or PET-CT data, description of metastatic sites, and information about the timing of recurrence after prior therapy. For choosing the first line of treatment, the details matter, not just the diagnosis itself.
Conclusion
The approval of Enhertu with pertuzumab as first-line treatment for unresectable or metastatic HER2-positive breast cancer will likely become one of the most notable changes in the treatment of this disease in recent years. It is very important for the patient to receive an accurate, personalized treatment plan from the start.
Frequently Asked Questions
Who is eligible for Enhertu with pertuzumab as first-line treatment?
According to the FDA approval, this applies to adult patients with unresectable or metastatic HER2-positive breast cancer, where HER2 status is confirmed by an approved test as IHC 3+ or FISH+.
How does the new regimen differ from the previous standard?
In the DESTINY-Breast09 study, median progression-free survival was 40.7 months with Enhertu plus pertuzumab versus 26.9 months with THP.
Does this mean the old standard is no longer needed?
No. The decision depends on the clinical situation, prior treatment, time to relapse, HER2 confirmation, and the patient's overall condition. However, the structure of first-line treatment is indeed changing after this approval.
Are there overall survival data available yet?
At the time of analysis in DESTINY-Breast09, overall survival data were still immature, although the interim signal favored the Enhertu plus pertuzumab combination.
More answers on the FAQ page.