DESTINY-Breast11 Trial Shows Enhertu Plus THP Significantly Improves Response Rates in High-Risk HER2-Positive Early Breast Cancer

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Topline results from the Phase III DESTINY-Breast11 trial (NCT05113251) show that Enhertu (trastuzumab deruxtecan; AstraZeneca and Daiichi Sankyo) followed by standard human epidermal growth factor receptor 2 (HER2)-targeted therapy produced a significant improvement in pathologic complete response (pCR) rates compared to current standard-of-care chemotherapy in patients with high-risk, locally advanced HER2-positive early-stage breast cancer. These findings demonstrate the promise of Enhertu as an alternative to anthracycline-based regimens for high-risk patients, according to investigators.^1,2

“The clinically meaningful improvement in pathologic complete response and the safety data seen in DESTINY-Breast11 highlight the potential of Enhertu to challenge the current standard of care in early-stage HER2-positive breast cancer,” said Susan Galbraith, executive vice president, Oncology Hematology R&D, AstraZeneca, in a press release. “Enhertu is already an important treatment option in the metastatic setting, and these data have the potential to allow this medicine to move into early stages of disease where cure is possible.”¹

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.^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

The drug has also been approved 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.⁴

Trial Design

The global, multicenter, randomized, open-label DESTINY-Breast11 trial analyzed the efficacy and safety of neoadjuvant Enhertu at a dose of 5.4 mg/kg monotherapy or Enhertu followed by paclitaxel, trastuzumab, and pertuzumab (THP) compared to a standard of care regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) in patients with high-risk, locally advanced or inflammatory HER2-positive early-stage breast cancer.

A total of 927 patients were randomly assigned in a 1:1:1 ratio to receive either eight cycles of Enhertu monotherapy; four cycles of Enhertu and then four cycles of THP; or four cycles of ddAC followed by four cycles of THP. The trial’s primary endpoint is pCR, with secondary endpoints that include event-free survival (EFS), invasive disease-free survival, overall survival, and safety.

Interim results show a statistically significant and clinically meaningful improvement in pCR among patients administered Enhertu followed by THP compared to ddAC. EFS data were not mature at the time of analysis but showed an early positive trend in favor of Enhertu plus THP compared to ddAC, according to trial investigators.

In terms of safety, the Enhertu plus THP combination showed a favorable profile vs. ddAC-THP. Adverse event reports were consistent with the previously established profiles for each individual medication and no new safety signals were reported. Detailed data from DESTINY-Breast11 will be shared at an upcoming medical meeting and submitted to regulatory authorities.

“There are still many patients with early-stage breast cancer who do not achieve a pathologic complete response with treatment in the neoadjuvant setting, increasing the risk of disease recurrence,” said Ken Takeshita, global head, R&D, Daiichi Sankyo, in the release. “These topline results from DESTINY-Breast11 demonstrate that Enhertu followed by THP could offer patients with HER2-positive breast cancer a promising new treatment approach prior to surgery, setting more patients on a path towards a potential cure."¹

References

1. Enhertu followed by THP before surgery showed statistically significant and clinically meaningful improvement in pathologic complete response in patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 Phase III trial. News release. AstraZeneca. May 7, 2025. Accessed May 7, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-improved-pcr-in-early-stage-breast-cancer.html#

2. Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer. ClinicalTrials.gov. Updated May 7, 2025. Accessed May 7, 2025. https://clinicaltrials.gov/study/NCT05113251

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 May 7, 2025

4. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed May 7, 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 May 7, 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