Breast Cancer VJToday

FDA approves trastuzumab deruxtecan plus pertuzumab for unresectable or metastatic HER2-positive breast cancer

On December 15, 2025, the U.S. Food and Drug Administration (FDA) approved trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate (ADC), with pertuzumab as first-line therapy for adults with unresectable or metastatic HER2-positive (HER2+) breast cancer.1 Despite significant improvements in outcomes with HER2-targeted agents over the past two decades, first-line therapy with a taxane and dual HER2 blockade has largely remained the same, with many patients still progressing quickly.2

The approval is based on results from the Phase III DESTINY-Breast09 trial (NCT04784715), which assessed the safety and efficacy of T-DXd with pertuzumab versus taxane, trastuzumab and pertuzumab (THP) in the first-line setting in patients with HER2+ advanced or metastatic breast cancer. 1157 patients were enrolled and were randomized 1:1:1 to receive T-DXd with pertuzumab, T-DXd with placebo, or THP.3

The primary endpoint of progression-free survival (PFS) assessed by blinded independent central review was met with a median PFS of 40.7 months (95% CI: 36.5-not estimable [NE]) for the T-DXd and pertuzumab arm versus 26.9 months (95% CI: 21.8-NE) for the THP arm. The PFS benefit was consistent across key clinical subgroups, including hormone receptor status and disease origin (de novo vs recurrent). While overall survival data remain immature, early trends suggest a favorable direction for the ADC plus pertuzumab combination. The safety profile observed in the trial was consistent with known effects of both agents, and no new safety signals were identified.3  

Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, Boston, MA, and principal investigator for the trial commented:

“We saw that the benefit of T-DXd clearly outweighed the benefits from THP therapy. And so it really showed there wasn’t a subgroup that was not benefiting and that it was very uniform in the benefits for the combination of T-DXd and pertuzumab.”

This regulatory approval represents the first new first-line option for HER2-positive metastatic breast cancer in over a decade and may shift the therapeutic paradigm by offering a targeted, potent alternative to conventional taxane-based regimens.

References:

  1. Center for Drug Evaluation and Research. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer  [Internet]. U.S. Food and Drug Administration. 2025 [cited 2025 Dec 15]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
  2. Wei C, Zheng Q, Ma X, Sun X, Wang Z, Tang S, et al. What is the optimal first-line regimen for patients with advanced HER2-positive breast cancer: A systematic review and network meta-analysis. Journal of Cancer Research and Therapeutics. 2025 Sep 1;21(4):875–85.
  3. Tolaney SM, Jiang Z, Zhang Q, Barroso-Sousa R, Park YH, Rimawi MF, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. Journal of Clinical Oncology. 2025 Jun 10;43(17_suppl).

Written by Sol Yohannes