HER2-Positive Breast Cancer: Enhertu and Pertuzumab Receive FDA Approval in the First Line
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First-Line Treatment Changes in Metastatic HER2-Positive Breast Cancer: FDA Approval of Enhertu + Pertuzumab
On 15 December 2025, the US Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu) and pertuzumab in combination for unresectable or metastatic HER2-positive breast cancer as first-line treatment . This decision concerns the standard used in HER2-positive disease for approximately 15 years: ‘taxane + trastuzumab + pertuzumab (THP)’ . For the first time, a development directly challenges and decisively surpasses this standard.
Key message: In HER2-positive metastatic breast cancer, a regimen based on an antibody–drug conjugate (ADC) now stands out as the first-line option providing the longest progression-free survival, in place of the chemotherapy + antibody triplet.
1) Why is this approval so important?
In HER2-positive metastatic breast cancer, first-line treatment determines the entire natural course of the disease. Since CLEOPATRA, the standard approach has been taxane + trastuzumab + pertuzumab (THP) . DESTINY-Breast09 is the first head-to-head trial to test this standard and demonstrate longer PFS in a Phase 3 setting.
2) DESTINY-Breast09 study design
The study enrolled patients who had not previously received, for metastatic disease, chemotherapy or HER2-targeted treatment — 1157 patients. Neoadjuvant or adjuvant HER2-targeted treatment had to have been completed at least 6 months earlier .
Patients were randomized 1:1:1 to three arms:
• Enhertu (5.4 mg/kg) + pertuzumab
• THP (docetaxel or paclitaxel + trastuzumab + pertuzumab)
• Experimental arm (not included in the FDA approval)
3) Primary Endpoint: PFS (median, months)
Hazard ratio (HR): 0.56 (95% CI: 0.44–0.71; p<0.0001). This means, in the risk of disease progression or death, a 44% relative reduction . PFS exceeding 40 months in metastatic disease is an extremely striking clinical gain.
4) Secondary Efficacy Results
| Endpoint | Enhertu + P | THP | Comment |
|---|---|---|---|
| ORR (objective response rate) | 87% | 81% | Higher and faster response |
| OS (overall survival) | Immature | — | Follow-up continues |
5) Safety: What Changed, and What Did Not?
The FDA label particularly emphasizes two issues: neutropenia and left ventricular dysfunction. This is not new for doctors familiar with HER2-targeted therapies, but close monitoring is required.
Interestingly, compared with taxane-containing THP, the potential for avoiding prolonged chemotherapy toxicity is considered a major advantage for patients’ quality of life.
Frequently Asked Clinical Questions
Will this decision change the guidelines?
Very likely. NCCN and ESMO updates are expected to include Enhertu + pertuzumab as a strong first-line option .
Does this apply to HER2-low patients?
No. This approval applies only to IHC 3+ or ISH+ HER2-positive patients.
Why are OS data not yet available?
OS takes time to mature in metastatic trials. However, a PFS difference of this magnitude has the potential to translate into OS as well.
DROZDOGAN Academy Commentary
With DESTINY-Breast09, in HER2-positive metastatic breast cancer, the ‘chemotherapy-based first-line’ paradigm has been seriously shaken. ADCs are becoming agents that operate not only in resistant disease, but also set the rules from the outset . In the coming years, the central debate will be: ‘For which patients is starting with an ADC the best strategy?’
Source: U.S. Food and Drug Administration, 15 December 2025; DESTINY-Breast09 (NCT04784715).
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