The antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan, T-DXd) has taken center stage as a new cornerstone in the treatment strategy for early-stage breast cancer.

Both the DESTINY-Breast05 and DESTINY-Breast11 trial results that were presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin showed significant results, positioning T-DXd as a potential new standard of care across both neoadjuvant (pre-surgical) and adjuvant (post-surgical) settings.


T-DXd reduces risk of recurrence by 53% compared to Kadcyla as postoperative adjuvant therapy

DESTINY-Breast05 is a Phase III head-to-head trial directly comparing Enhertu with the standard therapy Kadcyla (trastuzumab emtansine, T-DM1) in patients with HER2-positive early breast cancer who had residual invasive disease after neoadjuvant therapy (chemotherapy and targeted therapy before surgery).

Professor Dr. Charles E. Geyer of the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, who presented the data at ESMO, emphasized, “In high-risk patients with residual disease, T-DXd demonstrated a clear survival benefit over T-DM1.”

At the interim analysis, 3-year invasive disease-free survival (IDFS) was 92.4% for T-DXd (95% CI 89.9–94.4) versus 83.7% for T-DM1 (80.2–86.7), reflecting a 53% reduction in risk of events (HR 0.47, p<0.0001).

Similarly, disease-free survival (DFS) was 92.3% vs 83.5%, distant recurrence-free interval (DRFI) was 93.9% vs 86.1% (HR 0.49), and brain metastasis-free interval (BMFI) reached 97.6% vs 95.8%.

The 3-year overall survival (OS) rate was also higher with T-DXd (97.4% vs 95.7%), showing early separation of survival curves even at the early breast cancer stage.

Safety outcomes were comparable, with Grade ≥3 treatment-emergent adverse events (TEAEs) reported in 50.6% for T-DXd vs 51.9% for T-DM1. Drug-related ILD incidence was 9.6% for T-DXd (mostly grade 1–2; 2 grade 5 cases) and 1.6% for T-DM1, while treatment discontinuation due to ILD occurred in 10.8% of T-DXd and 2.5% of T-DM1.

Pressor Geyer noted, “Most ILD cases were mild and reversible with early recognition and intervention. With appropriate monitoring and management, ILD is fully manageable.”

He concluded, “T-DXd has demonstrated clear benefits in terms of both IDFS and DFS for high-risk HER2-positive patients and has the potential to replace T-DM1 as a new standard of care.”

# Also shows superiority as preoperative neoadjuvant therapy… “T-DXd-THP is safer and stronger”

The DESTINY-Breast11 (291O) trial, also announced that day, compared standard ddAC-THP with T-DXd monotherapy (8 cycles) or T-DXd (4 cycles) followed by paclitaxel, Herceptin (trastuzumab), and Perjeta (pertuzumab) combination therapy (T-DXd-THP).

Results showed a pathological complete response (pCR) rate of 67.3% vs. 56.3%, representing a statistically significant 11.2 percentage point improvement (p=0.003). A trend toward improved event-free survival (EFS) was also observed (HR 0.56, maturity 4.5%).

Consistent superiority was confirmed in both hormone receptor-positive (HR+) patients (61.4% vs 52.3%) and hormone receptor-negative (HR–) patients (83.1% vs 67.1%).

Regarding safety, Grade ≥3 adverse events were lower in T-DXd-THP (37.5%) vs ddAC-THP (55.8%), and left ventricular dysfunction was 1.9% vs 9.0%. Drug-related ILD was comparable at 4.4% vs 5.1%.

Professor Nadia Harbeck of Ludwig Maximilian University Hospital, Munich, who presented the data, explained, “T-DXd-THP demonstrated a statistically significant improvement in pCR compared to standard therapy with lower toxicity. It could become a compelling option for anthracycline-free neoadjuvant therapy.”

“Discussion on timing of use—before vs. after surgery—will begin”
Dr. Sara Tolaney of Dana-Farber Cancer Institute commented that, “T-DXd retains the same antibody backbone as T-DM1 but incorporates a more potent payload and bystander effect, representing a key structural evolution.”

She added, “Despite including a higher-risk population than the historic KATHERINE trial, DESTINY-Breast05 achieved significant survival improvements, underscoring its strong clinical relevance.”

Experts anticipate that the timing of T-DXd administration will become a key point of discussion in future clinical practice.

Sara Hurvitz, Professor at the Fred Hutch Cancer Center and the University of Washington, stated, “Whether to use it as neoadjuvant or as postoperative adjuvant therapy will be central to future discussions. At this point, the evidence for its use as adjuvant therapy, particularly in patients with residual disease after chemotherapy, is more robust.”

At the congress, Professor Yeon-Hee Park, Professor of Hematology-Oncology at Samsung Medical Center, said, “Enhertu has already been an established therapy in metastatic breast cancer, but these new DESTINY-Breast05 results demonstrate its significant efficacy even in early-stage disease. In Korea, discussions on incorporating it into clinical practice for post-surgical residual disease or high-risk patients will likely proceed rapidly.”

She added, “Although DESTINY-Breast11 has interpretive limitations due to its design, it opens new discussions on toxicity management and combination strategies. Enhertu (T-DXd) could demonstrate greater clinical value in patient populations where Kadcyla (T-DM1) fell short.”