Compelling evidence presented at the European Society of Medical Oncology (ESMO) Congress, being held October 17-21, 2025, in Berlin, Germany, has shown that a new generation of antibody-drug conjugates (ADCs) can dramatically improve outcomes for patients with early-stage HER2-positive breast cancer.
The results from the phase 3 DESTINY-Breast05 (NCT04622319) and the DESTINY-Breast11 (NCT05113251) trials, presented in a Presidential Symposium, mark a paradigm shift in breast cancer treatment, positioning ADCs not only as powerful therapeutic agents when the disease has already progressed but also as potential new standards of care in patients with early disease [1][2]
“There is a particular need for therapies to ensure patients with HER2-positive early breast cancer achieve pathological complete response following neoadjuvant therapies, and a high unmet need to treat residual disease in those who do not, to prevent the development of metastasis,” explained Evandro de Azambuja, MD, Ph.D, who leads the Medical Support Team at the Jules Bordet Institute in Brussels, Belgium.
Currently, trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) is the only ADC approved for patients with HER2-positive early breast cancer who show residual invasive disease after neoadjuvant therapy and are at a high risk of recurrence. [3[
In the DESTINY-Breast05, Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca), a new-generation ADC delivering a topoisomerase I inhibitor, demonstrated that it improvea invasive disease-free survival and disease-free survival by 53% compared with T-DM1 (for both: hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.34–0.66; p<0.0001). Also, T-DXd confirmed its high brain activity, demonstrating a clinically meaningful improvement in brain metastasis-free interval over T-DM1 (HR 0.64; 95% CI 0.35–1.17).
A new standard of care
“The generally manageable safety profile and the superior efficacy data suggest that T-DXd should replace T-DM1 as the new standard of care for patients with HER2-positive, residual invasive breast cancer after neoadjuvant therapy,” noted De Azambuja.
The use of T-DXd also showed impressive findings earlier in the treatment pathway— before surgery— as reported in the DESTINY-Breast11 trial where 927 untreated patients with high-risk HER2-positive early breast cancer received either the ADC followed by standard HER2-targeted therapy (THP) or the conventional anthracycline-based regimen (ddAC-THP).
The cycles of T-DXd, sequenced with THP, led to a significant increase in the rate of pathological complete response at surgery (67.3% versus 56.3%; p=0.003).
An improved safety profile
“The T-DXd regimen has also the added advantage of an improved safety profile compared with the anthracycline-containing regimen,” explained De Azambuja, adding that “the relevant reduction in cardiac toxicities which was observed with the ADC compared with the conventional treatment.”
“In conjunction, these two studies establish T-DXd as a critical treatment option for early-stage HER2-positive breast cancer, ultimately providing a new tool for treatment tailoring for what was once considered the most aggressive subtype of breast cancer, and which today represents the one with the highest chance of cure,” highlights Paolo Tarantino, MD, who is an advanced research fellow in the Breast Oncology Program at Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA, and affiliated with the European Institute of Oncology, and the University of Milan, Italy.
After having reshaped the treatment of multiple types of metastatic cancers over the last few years, novel ADCs such as T-DXd are now, without a doubt, raising the bar in the curative setting due to innovations in their design and mechanism of action. However, their use presents new challenges that need to be addressed.
“For instance, toxicity profiles must be carefully defined and substantial effort to prevent permanent or fatal toxicities is required. Dosing, duration and sequencing of ADCs must also be optimised to achieve maximal efficacy with the least side-effects, and equally critical is the identification of predictive biomarkers that may allow better tailoring of ADC therapy and minimise overtreatment,” Tarantino explained.
Smarter, earlier, deeper, broader… better?
With a new generation of ADCs now demonstrating superiority in both pre- and post-surgical settings, the oncology community stands at the threshold of a new chapter—one defined by smarter targeting, earlier intervention and deeper biological understanding.
“Besides the immediate practical impact, in fact, data presented are expected to have a broader impact on the future of ADC research, marking the formal entrance of the new generation of drugs in the curative arena. This is a therapeutic strategy with tremendous potential, which we are only just starting to unleash, promising to reduce rates of recurrence and improve survival across multiple cancers in the years to come,” Tarantino, concluded.
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Clinical trials
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 ID NCT04622319
Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer
ClinicalTrials.gov ID NCT05113251
Highlights of Prescribing information
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)[Prescribing Information]
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Reference
[1] Geyer C, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): Interim analysis of DESTINY-Breast05. LBA1 presented at the ESMO Congress 2025, Presidential Simposium I on Saturday, 18 October, 16:30-18:15, Berlin Auditorium-Hub 27.
[2] Abstract 291O – Harbeck N, et al. DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC). ESMO Congress 2025 ì, Presidential Simposium I on Saturday, 18 October, 16:30-18:15, Berlin Auditorium-Hub 27.
[3] FDA approves ado-trastuzumab emtansine for early breast cancer. U.S. Food and Drug Administration. 3 May 2019. Online. Last accessed on October 14, 2025.
This article was first published in ADC Review | J. Antibody-drug Conjugates on October 19, 2025.
Featured image: ESMO 2025; Berlin Germany. Photo courtesy © 2025 European Society of Medical Oncology (ESMO. Used with permission.
DOI
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