Emerging Trends in HER2-Positive Breast Cancer Treatment: Insights from DESTINY-Breast09

The landscape of treatment for HER2-positive breast cancer is undergoing significant transformation, particularly following the results from the phase 3 DESTINY-Breast09 trial (NCT04784715). According to Dr. Hope S. Rugo, a prominent figure in oncological research and the director of the Women’s Cancers Program at City of Hope, the trial has brought to light the potential of antibody-drug conjugates (ADCs) to establish new standards in early-stage management of this disease.

The DESTINY-Breast09 trial investigated the combination of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) as a first-line treatment option. Results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting revealed that patients receiving this combination therapy had a median progression-free survival (PFS) of 40.7 months, compared to 26.9 months for those treated with the traditional regimen of trastuzumab (Herceptin) plus pertuzumab and a taxane (THP). This marked improvement, with a hazard ratio of 0.56 (P < 0.00001), underscores the efficacy of T-DXd in the treatment of HER2-positive breast cancer.

Dr. Rugo emphasized the implications of these findings, stating, "Patients receiving T-DXd plus pertuzumab had a better response and a remarkably longer relative improvement in PFS." However, she also raised critical questions regarding the clinical applications of these results. For instance, the necessity of pertuzumab in conjunction with T-DXd remains uncertain until data from the T-DXd monotherapy arm can be analyzed, as the current findings do not provide a definitive answer.

The trial's findings have sparked discussions regarding maintenance therapies and the integration of endocrine and CDK4/6 inhibitors to enhance patient outcomes. Notably, the percentage of patients who discontinued T-DXd due to adverse effects was lower compared to those in the THP arm, highlighting the potential for improved tolerability with the newer ADC-based regimen.

Looking ahead, Dr. Rugo noted that ongoing and upcoming trials such as DESTINY-Breast11 (NCT05113251) and the DEMETER trial (NCT06172127) will further explore the combinations of T-DXd with other therapies, including CDK4/6 inhibitors, to optimize treatment strategies for patients with hormone receptor-positive HER2-positive breast cancer. These studies could lead to a shift in standard treatment protocols, potentially improving patient survival rates.

In a broader context, the developments stemming from the DESTINY-Breast09 trial reflect a significant shift in the management of HER2-positive breast cancer. The integration of ADCs into earlier treatment lines is poised to enhance clinical outcomes substantially. As noted in the 2023 publication by Tolaney et al. in the Journal of Clinical Oncology, the evolution of ADCs continues to provide promising avenues for therapy, particularly for those patients with advanced disease.

As the medical community awaits further data from ongoing research and additional trials, the potential for T-DXd and other ADCs to redefine treatment standards remains a focal point of discussion among oncologists. The implications of these findings extend beyond immediate clinical applications, as they may influence future therapeutic strategies and ultimately improve the quality of life for patients battling HER2-positive breast cancer.