DESTINY-Breast09 Trial Shows Enhertu Plus Perjeta Significantly Improves Survival in HER2-Positive Metastatic Breast Cancer
In the Phase III DESTINY-Breast09 trial, Enhertu (trastuzumab deruxtecan) and Perjeta (pertuzumab) significantly improved progression-free survival compared to the current standard of care in the first-line treatment of HER2-positive metastatic breast cancer, suggesting a potential new standard of care.
Credit: Sebastian Kaulitzki | stock.adobe.com
Interim data from the Phase III DESTINY-Breast09 trial (NCT04784715) found that the combination of Enhertu (trastuzumab deruxtecan; AstraZeneca and Daiichi Sankyo) plus Perjeta (pertuzumab) produced a significant improvement in progression-free survival (PFS) treating HER2-positive metastatic breast cancer (MBC) compared to the current first-line standard of care regimen of a taxane, Herceptin (trastuzumab), and Perjeta (THP).1,2 These results could represent a major potential shift in the current treatment paradigm for patients with HER2-positive MBC, according to trial investigators.
“This is the first trial in more than a decade to demonstrate superior efficacy across a broad HER2-positive metastatic breast cancer patient population compared to the current first-line standard of care,” said Susan Galbraith, executive vice president, Oncology Hematology R&D, AstraZeneca, in a press release. “This is a significant milestone for patients and sets the foundation for Enhertu in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting.”1
Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate. Its mechanism of action 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 apoptotic cell death as a topoisomerase I inhibitor.3,4
In April 2024, the FDA granted accelerated approval to Enhertu for adults with unresectable or metastatic HER2-positive, IHC 3+ solid tumors who were previously administered systemic therapy and who have no satisfactory alternative treatment options. The approval was based on findings from the Phase II DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials.5
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.6
Trial Design
The global, multicenter, randomized, open-label, DESTINY-Breast09 trial is being conducted at multiple sites in Africa, Asia, Europe, North America, and South America. Investigators are evaluating the efficacy and safety of Enhertu at a dose of 5.4 mg/kg both as monotherapy and combined with Perjeta compared to THP comprised of docetaxel or paclitaxel with Herceptin and Perjeta in the first line treatment of patients with HER2-positive MBC.
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 is 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 (OS); objective response rate; duration of response; investigator-assessed time to second progression or death; patient-reported tolerability; pharmacokinetics; and safety.
The significant improvement in PFS was observed across all pre-specified patient subgroups administered Enhertu plus Perjeta. OS data were not mature at the time of the planned interim analysis, but the interim data demonstrated an early trend in favor of Enhertu plus Perjeta compared to THP.
In terms of safety, the profile of the Enhertu plus Perjeta combination was consistent with prior findings with each individual therapy and no new safety signals were reported. Full data from DESTINY-Breast09 will be presented at an upcoming medical meeting and submitted to regulatory authorities.
“The results from DESTINY-Breast09 reinforce the importance of effectively targeting HER2 to achieve durable disease control early in the treatment of HER2-positive metastatic breast cancer,” said Ken Takeshita, Global Head, R&D, Daiichi Sankyo, in a press release. “Building on the positive results seen with Enhertu in the second-line setting, these new findings suggest that starting treatment with Enhertu in combination with pertuzumab at the time of metastatic diagnosis delays disease progression, postponing the time until additional treatment may be needed.”1
References
1. Enhertu plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival vs. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer. AstraZeneca. News release. April 21, 2025. Accessed April 21, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-combination-improved-pfs-in-1l-her-positive-mbc.html#!
2. Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated December 16, 2024. Accessed April 21, 2025. https://clinicaltrials.gov/study/NCT04784715
3. 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 April 21, 2025.
4. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed April 21, 2025.
5. ENHERTU Approved in the U.S. as First Tumor Agnostic HER2 Directed Therapy for Previously Treated Patients with Metastatic HER2 Positive Solid Tumors. News Release. Tokyo: Daiichi Sankyo; April 5, 2024. Accessed April 21, 2025. https://daiichisankyo.us/press-releases/-/article/enhertu-approved-in-the-u-s-as-first-tumor-agnostic-her2-directed-therapy-for-previously-treated-patients-with-metastatic-her2-positive-solid-tumors
6. Perjeta. Webpage. BreastCancer.org. Updated March 4, 2025. Accessed April 21, 2025. https://www.breastcancer.org/treatment/targeted-therapy/perjeta
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