DESTINY-Breast05 Phase III Trial Demonstrates ENHERTU® Significantly Reduces Recurrence Risk in High-Risk HER2-Positive Early Breast Cancer
Positive results from the DESTINY-Breast05 Phase III trial have demonstrated that ENHERTU® (fam-trastuzumab deruxtecan-nxki) provides a highly statistically significant and clinically meaningful improvement in invasive disease-free survival (IDFS) for patients with high-risk HER2-positive early breast cancer. This trial specifically evaluated patients who had residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant therapy, comparing ENHERTU to the standard post-neoadjuvant treatment, trastuzumab emtansine (T-DM1).
The trial’s results are particularly noteworthy: ENHERTU reduced the risk of invasive disease recurrence or death by 53% compared with T-DM1, with an IDFS hazard ratio (HR) of 0.47 (95% confidence interval [CI] 0.34–0.66; p<0.0001). At the three-year mark, 92.4% of patients receiving ENHERTU remained alive and free from invasive disease, compared to 83.7% in the T-DM1 group. Importantly, these benefits were consistent across all prespecified subgroups, suggesting broad applicability within the high-risk population.
Beyond IDFS, ENHERTU also demonstrated a 53% reduction in the risk of disease recurrence or death, measured by disease-free survival (DFS), a key secondary endpoint (HR 0.47; 95% CI 0.34–0.66; p<0.0001). Additionally, ENHERTU lowered the risk of distant disease recurrence (distant recurrence-free interval [DRFI]) by 51% and the risk of brain metastases (brain metastasis-free interval [BMFI]) by 36% compared with T-DM1. While overall survival (OS) data remain immature at this interim analysis (with 2.9% maturity at data cut-off), initial trends are promising (HR 0.61; 95% CI 0.34–1.10).
Dr. Charles Geyer, MD, Chief Scientific Officer of the NSABP Foundation and principal investigator for DESTINY-Breast05, emphasized the clinical importance of these findings: “For patients with residual disease after neoadjuvant treatment, the post‑neoadjuvant setting represents a critical second opportunity to reduce recurrence risk. ENHERTU reduced the risk of early recurrence or death by 53% compared to T‑DM1. These results, along with the safety data, are likely to transform clinical practice for high-risk patients, potentially establishing ENHERTU as a new standard of care.”
Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, highlighted the broader impact on early-stage breast cancer treatment: “Progress in managing HER2-positive early breast cancer has been substantial, but patients at higher risk of recurrence remain challenging. These landmark data, along with those from DESTINY-Breast11, underscore ENHERTU’s potential as a foundational treatment in early-stage disease, offering more patients a chance for cure.”
Ken Takeshita, Global Head of R&D at Daiichi Sankyo, added: “The results of DESTINY-Breast05 demonstrate a clear benefit of ENHERTU over the current standard of care following surgery, improving chances for sustained long-term outcomes. Combined with DESTINY-Breast11, these findings illustrate the promise of moving ENHERTU earlier in the treatment paradigm, where it can have the greatest impact on patient lives.”
Summary of Key Efficacy Results (DESTINY-Breast05)
| Efficacy Measure | ENHERTU (5.4 mg/kg; n=818) | T-DM1 (n=817) | HR (95% CI) |
|---|---|---|---|
| IDFS, 3-year rate | 92.4% | 83.7% | 0.47 (0.34–0.66); p<0.0001 |
| DFS, 3-year rate | 92.3% | 83.5% | 0.47 (0.34–0.66); p<0.0001 |
| DRFI, 3-year event-free rate | 93.9% | 86.1% | 0.49 (0.34–0.71) |
| BMFI, 3-year event-free rate | 97.6% | 95.8% | 0.64 (0.35–1.17) |
| OS, 3-year survival | 97.4% | 95.7% | 0.61 (0.34–1.10) |
The safety profile observed in DESTINY-Breast05 was consistent with prior studies of ENHERTU, with no new safety concerns identified. Grade 3 or higher treatment-emergent adverse events occurred at similar rates in both arms (ENHERTU 50.6% vs. T-DM1 51.9%). Interstitial lung disease (ILD) events were infrequent, occurring in 9.6% of patients receiving ENHERTU, mostly Grades 1–2, compared to 1.6% in the T-DM1 arm. Seven Grade 3 ILD events were reported with ENHERTU, with no Grade 4 events and two Grade 5 events adjudicated by an independent committee.
DESTINY-Breast05, conducted in collaboration with NSABP, the German Breast Group, AGO-B, and SOLTI, marks a pivotal step in the development of ENHERTU, a HER2-directed antibody-drug conjugate (ADC) developed by Daiichi Sankyo and AstraZeneca. ENHERTU’s design allows targeted delivery of a topoisomerase I inhibitor to HER2-expressing cancer cells, maximizing anti-tumor activity while maintaining manageable toxicity.
ENHERTU is already approved for various HER2-positive and HER2-low breast cancers, HER2-mutant non-small cell lung cancer (NSCLC), HER2-positive gastric or gastroesophageal junction adenocarcinoma, and other HER2-positive solid tumors. Its safety profile includes risks of ILD/pneumonitis, neutropenia, left ventricular dysfunction, and embryo-fetal toxicity. Patients are monitored for early signs of ILD, infections, hematologic abnormalities, and cardiac function, with dose modifications and treatment interruptions applied as needed.
Common adverse reactions across ENHERTU trials include nausea, decreased white blood cell count, fatigue, anemia, alopecia, vomiting, diarrhea, and elevated liver enzymes. Most side effects are manageable with dose adjustments and supportive care. The treatment has been studied extensively in HER2-positive, HER2-low, and HER2-ultralow breast cancer populations, as well as in NSCLC and gastric cancer, showing consistent efficacy and tolerability across different patient subgroups.
ENHERTU’s approval in various indications is under accelerated pathways in some cases, based on response rates and duration of response, with continued approval contingent on confirmatory trials. Physicians are advised to carefully monitor patients for ILD, hematologic toxicity, and cardiac function, and to counsel patients on reproductive risks, as ENHERTU can cause embryo-fetal harm.
