At the 2025 ASCO Annual Meeting, the DESTINY-Breast09 results were presented (Abstract LBA1008). Researchers aimed to determine whether T-DXd could improve patient outcomes in the first-line setting in the DESTINY-Breast09 clinical trial. Results indicated that T-DXd + Pertuzumab may provide a new first-line standard of therapy for metastatic HER2-positive breast cancer, a disease that has not witnessed any advancement in over ten years.  A taxane used in combination with the HER2-targeted therapy like trastuzumab and pertuzumab (THP) has been the accepted first-line treatment for patients with locally advanced or metastatic HER2-positive breast cancer for over 20 years. Nonetheless, within 2 years of treatment the majority of THP patients develop cancer. 

Among the patients randomized to trastuzumab deruxtecan plus pertuzumab (T-DXd + P; n = 383) and trastuzumab, pertuzumab, and a taxane (THP; n = 387), 52% had de novo disease and 54% had hormone receptor–positive (HR+) status. Baseline demographic and disease characteristics were well balanced between the groups.

At a median follow-up of nearly 2.5 years (29 months; interim data cutoff February 26, 2025); T-DXd + P significantly improved PFS by blinded independent central review (BICR; hazard ratio, 0.56; 95% confidence interval [CI], 0.44–0.71; p<0.00001). This combo reduced the risk of disease progression or death by 44% for patients.  The median progression-free survival was more than 3 years with T-DXd and pertuzumab (40.7 months).

Roughly 70% of patients in the T-DXd with pertuzumab group experienced no growth or spread of their cancer at 2 years, compared to roughly 52% in the THP group. About 85% of individuals who received T-DXd with pertuzumab achieved a reduction or disappearance of their cancer, compared to 78.6% of patients in the THP group. Approximately 15% of patients who responded to T-DXd plus pertuzumab treatment showed no evidence of malignancy, compared to 8.5% in the THP group. Although overall survival (OS) data was still not mature, researchers observed a pattern of OS improvement for patients receiving T-DXd with pertuzumab. 

Both groups experienced similar rates of serious adverse effects. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 63.5% of patients receiving T-DXd + P and 62.3% of those receiving THP. Serious TEAEs were reported in 27.0% and 25.1% of patients, respectively. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis was observed in 46 patients (12.1%) in the T-DXd + P arm—predominantly Grade 1/2, with two cases (0.5%) of Grade 5—and in 4 patients (1.0%) in the THP arm, all Grade 1/2.

KOL insights: 

“The combination of T-DXd and pertuzumab demonstrated a statistically significant and clinically meaningful improvement in PFS compared with THP. These data suggest that the combination of T-DXd and pertuzumab may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer.”– Expert Opinion

“The findings from Destiny-Breast09 represent a new first-line standard treatment option for HER2-positive metastatic breast cancer. The duration of therapy can now be measured in years and gives us the opportunity to look at appropriate sequencing of this new standard to optimize quality of life and toxicities”– Expert Opinion

Conclusion: 

The DESTINY-Breast09 trial introduces trastuzumab deruxtecan (T-DXd) into the frontline treatment setting for HER2-positive advanced or metastatic breast cancer, challenging the conventional paradigm that relies on taxane-based induction chemotherapy. Unlike taxanes, T-DXd is not associated with cumulative neurotoxicity, making it a compelling option for extended use and potentially improving long-term tolerability. In combination with pertuzumab, T-DXd significantly improved PFS compared to the standard THP regimen. This benefit was both statistically significant and clinically meaningful, with consistent results observed across all patient subgroups, highlighting the robustness and generalizability of the findings. The data suggests that T-DXd plus pertuzumab could potentially redefine the first-line treatment landscape for HER2-positive advanced or metastatic breast cancer, offering a combination of enhanced efficacy with a favorable safety and tolerability profile.