Could ADCs become the new standard of care for HER2+ breast cancer?
Results from the Phase III DESTINY-Breast05 and DESTINY-Breast11 trials indicate that antibody-drug conjugates (ADCs) may significantly improve outcomes in patients with HER2-positive early breast cancer.
Two pivotal studies presented at ESMO 2025 (17–21 October, Berlin, Germany) have demonstrated that trastuzumab deruxtecan (T-DXd), a new-generation ADC delivering a topoisomerase I inhibitor, was highly effective both before surgery and for early-stage disease.
“There is a particular need for therapies to ensure patients with HER2-positive early breast cancer achieve pathological complete response following neoadjuvant therapies – i.e., delivered before surgery – and a high unmet need to treat residual disease in those who do not, to prevent the development of metastasis,” explained Evandro de Azambuja from the Jules Bordet Institute (Brussels, Belgium), which participated in DESTINY-Breast05.
T-Dxd before surgery
DESTINY-Breast05 compared T-Dxd to trastuzumab emtansine (T-DM1), currently 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. This study reported that T-Dxd improved invasive disease-free survival and disease-free survival by 53% compared with T-DM1 as well as demonstrating a clinically meaningful improvement in brain metastasis-free interval.
“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.
T-Dxd in early-stage breast cancer
The potential of T-Dxd was cemented in the DESTINY-Breast11, which trialed T-Dxd in untreated patients with high-risk HER2-positive early breast cancer. In this study, cycles of T-DXd, sequenced with the standard HER2-targeted therapy, led to a significant increase in the rate of pathological complete response at surgery, at 67.3%, compared with the conventional anthracycline-based regimen, at 56.3%.
“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,” highlighted Paolo Tarantino from the Dana-Farber Cancer Institute and Harvard Medical School (both MA, USA).
The future of ADCs in cancer care
Although ADCs have shown promise in these studies and others, there is still work needed to tune optimal ADC dosing, duration and sequencing to balance their positive effects with potential toxicity.
“Besides the immediate practical impact, in fact, data presented today 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,” concluded Tarantino.