FDA Approves Enhertu Plus Perjeta as First-Line Therapy for HER2-Positive Metastatic Breast Cancer

The FDA has approved Enhertu (fam-trastuzumab deruxtecan-nxki; AstraZeneca and Daiichi Sankyo) plus Perjeta (pertuzumab) for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer. The regulatory action marks the first new treatment approved in over a decade for the first-line treatment of HER2-positive breast cancer.¹

Regulatory Decision Expands First-Line Options in HER2-Positive Disease

“Since its initial approval six years ago, Enhertu has transformed the treatment of HER2 positive metastatic breast cancer,” Ken Keller, global head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc, said in a press release. “With this approval in the first-line metastatic setting, Enhertu once again offers significant improvements in progression-free survival and has practice-changing potential when used in combination with pertuzumab.”¹

Enhertu Mechanism of Action as a HER2-Directed Antibody–Drug Conjugate

• Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate.
• It has a mechanism of action that involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd.
• Trastuzumab then attaches to HER2 on tumor cells to inhibit growth, which causes the antibody to be internalized as lysosomal enzymes cleave off DXd.
• Subsequently, DXd causes DNA damage as it replicates and causes apoptotic cell death as a topoisomerase I inhibitor.^2,3
• Enhertu holds approved indications across cancer types, including for patients with unresectable or metastatic HR-positive, HER2-low, or HER2-ultralow breast cancer; patients with unresectable or metastatic non-small cell lung cancer whose tumors have activating HER2 mutations; patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma previously administered a trastuzumab-based regimen; and patients with unresectable or metastatic HER2-positive solid tumors previously administered systemic therapy and who have no satisfactory alternative treatment options.³

Role of Perjeta in HER2 Pathway Inhibition

• Perjeta is a targeted HER2 inhibitor that attaches to HER2 receptors on the surface of breast cancer cells and stops them from receiving growth signals.
• Perjeta has also been found to inhibit breast cancer development by alerting the immune system to attack and destroy cancer cells that the drug attached to.⁴

DESTINY-Breast09 Trial Design and Patient Population

• The global, multicenter, randomized, open-label, DESTINY-Breast09 trial was conducted at multiple sites in Africa, Asia, Europe, North America, and South America.
• Investigators compared Enhertu at a dose of 5.4 mg/kg both as monotherapy and combined with Perjeta vs. the current first-line standard of care regimen of a taxane—docetaxel or paclitaxel—Herceptin (trastuzumab), and Perjeta (THP) in the first line treatment of patients with HER2-positive metastatic breast cancer.
• A total of 1,157 patients were randomly assigned in a 1:1:1 ratio to receive either Enhertu alone plus a Perjeta matching placebo, Enhertu plus Perjeta, or THP.
• Patient randomization was stratified based on previous therapy involving de novo metastatic disease versus progression from early-stage disease; hormone receptor status; and PIK3CA mutation status.
• The trial’s primary endpoint was PFS as evaluated by blinded independent central review in the Enhertu monotherapy cohort and Enhertu combination cohort.
• Key secondary endpoints include investigator-assessed PFS; overall survival; objective response rate (ORR); duration of response; investigator-assessed time to second progression or death; patient-reported tolerability; pharmacokinetics; and safety.

Progression-Free Survival and Response Outcomes

• Results from the trial show Enhertu plus Perjeta lowered the risk of disease progression or death by 44% compared to THP in patients with HER2 positive disease who were not previously administered chemotherapy or HER2 targeted therapy or who had received neoadjuvant or adjuvant HER2 targeted therapy greater than six months prior to being diagnosed with advanced or metastatic disease.¹
• Median PFS was 40.7 months with Enhertu plus Perjeta compared to 26.9 months with THP as assessed by blinded independent central review.
• Confirmed ORR was 87% in the Enhertu plus Perjeta cohort compared to 81% with THP.

“Trastuzumab deruxtecan plus pertuzumab is the only first-line treatment approved in more than a decade to demonstrate a statistically significant improvement in progression-free survival over the current standard regimen for patients with HER2 positive metastatic breast cancer,” DESTINY-Breast09 trial principal investigator Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology, Dana-Farber Cancer Institute, said in the press release. “With a median progression-free survival exceeding three years versus approximately two years with THP, trastuzumab deruxtecan combined with pertuzumab should become a new first-line standard of care in this setting.”¹

References

1. ENHERTU® Plus Pertuzumab Approved in the U.S. as First New Treatment in More Than a Decade for First-Line Treatment of Patients with HER2 Positive Metastatic Breast Cancer. News release. AstraZeneca. December 15, 2025. Accessed December 15, 2025. https://www.businesswire.com/news/home/20251210874349/en/ENHERTU-Plus-Pertuzumab-Approved-in-the-U.S.-as-First-New-Treatment-in-More-Than-a-Decade-for-First-Line-Treatment-of-Patients-with-HER2-Positive-Metastatic-Breast-Cancer

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed December 15, 2025.

3. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed December 15, 2025.

4. Perjeta. Webpage. BreastCancer.org. Updated November 14, 2025. Accessed December 15, 2025. https://www.breastcancer.org/treatment/targeted-therapy/perjeta