T-DXd Yields iDFS Improvement vs T-DM1 in High-Risk HER2+ Early Breast Cancer After Neoadjuvant Therapy

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu; AstraZeneca) generated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) compared with ado-trastuzumab emtansine (Kadcyla; T-DM1) in patients with HER2-positive early breast cancer with residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy and a high risk of disease recurrence, according to data from a planned interim analysis of the phase 3 DESTINY-Breast05 trial (NCT04622319).1

At the time of this interim analysis, overall survival (OS) data were not mature and will be assessed at a subsequent analysis. However, the safety profile of T-DXd observed in this analysis of DESTINY-Breast05 was consistent with its known profile, with no new adverse effects identified.

This represents the second positive phase 3 trial of T-DXd in the early-stage setting of HER2-positive breast cancer following the May 2025 announcement of results from the phase 3 DESTINY-Breast11 trial (NCT05113251), which evaluated T-DXd followed by trastuzumab (Herceptin), pertuzumab (Perjeta), and paclitaxel (THP) in the neoadjuvant setting.2

“[DESTINY-Breast05] is the first to directly compare [T-DXd] and T-DM1 in early breast cancer, and the results clearly show that [T-DXd] delivers superior outcomes, indicating that it may be a better option for patients with high-risk HER2-positive disease in the post-neoadjuvant setting,” Susan Galbraith, MBBChir, PhD, executive vice president of oncology R&D at AstraZeneca, stated in a news release.1 “These results from DESTINY-Breast05, coupled with DESTINY-Breast11, underscore our commitment to moving [T-DXd] into early-stage HER2-positive breast cancer, where patients can achieve sustained long-term outcomes, increasing the opportunity for cure.”

Findings from both DESTINY-Breast05 (Abstract LBA1) and DESTINY-Breast11 (Abstract 291O) are scheduled for presentation during Presidential Symposium 1 on October 18 at the upcoming 2025 ESMO Congress. Findings from DESTINY-Breast05 will be submitted to global regulatory authorities.

“In patients with early breast cancer with residual disease following neoadjuvant treatment, it is critical to optimize treatment as this represents the last opportunity to prevent progression to metastatic disease,” Ken Takeshita, global head of R&D at Daiichi Sankyo, added in a news release.2 ‘The results of DESTINY-Breast05 demonstrate that treatment with [T-DXd] following surgery increases the length of time patients are able to live free of invasive disease compared to the existing standard of care, potentially offering patients with HER2-positive early breast cancer a new treatment approach in this curative-intent setting."

How Was the DESTINY-Breast05 Trial Designed?

The multicenter, randomized, open-label, active-controlled study enrolled patients 18 years and older with pathologically documented breast cancer with a HER2 expression of immunohistochemistry 3+ and/or in situ hybridization positive.3 Patients needed to have T1-4, N0-3, M0 disease, and those with T1N0 tumors were excluded from enrollment.

Patients also needed to have evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes after neoadjuvant therapy comprising taxane-based chemotherapy and HER2-directed therapy. Adequate excision confirmed by medical records was required, defined as surgical removal of all clinically evident disease in the breast and axillary lymph nodes; patients were not allowed to have an interval of more than 12 weeks between the date of last surgery and the date of randomization. An ECOG performance status of 0 or 1 and adequate organ function were also required.

Investigators randomly assigned patients to receive T-DXd at 5.4 mg/kg once every 3 weeks or T-DM1 at 3.6 mg/kg once every 3 weeks.

Along with the primary end point of iDFS, secondary end points included DFS, OS, distant recurrence-free survival, brain metastases–free survival, safety, and pharmacokinetics.

References

1. Enhertu demonstrated highly statistically significant and clinically meaningful improvement in invasive disease-free survival vs. T-DM1 in DESTINY-Breast05 phase III trial in patients with high-risk early breast cancer following neoadjuvant therapy. News release. AstraZeneca. September 29, 2025. Accessed September 29, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-improved-idfs-in-early-bc-in-db-05.html
2. Enhertu (fam-trastuzumab deruxtecan-nxki) 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 September 29, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-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.html
3. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated May 9, 2025. Accessed September 29, 2025. https://clinicaltrials.gov/study/NCT04622319