Emerging Strategies in HER2+ Breast Cancer: Insights from DESTINY-Breast09

In July 2025, the American Society of Clinical Oncology (ASCO) Annual Meeting showcased pivotal findings from the DESTINY-Breast09 trial, which evaluated the efficacy of fam-trastuzumab deruxtecan-nxki (T-DXd) in combination with pertuzumab for first-line treatment of HER2-positive metastatic breast cancer. The trial, which involved 770 patients, revealed a significant improvement in median progression-free survival (PFS) of 40.7 months for those receiving T-DXd plus pertuzumab, compared to 26.9 months with the traditional regimen of trastuzumab, pertuzumab, and a taxane (THP).

Dr. Laura Huppert, an assistant professor of medicine at the University of California, San Francisco, who presented the findings, emphasized the implications of the results. She stated, "The efficacy benefit observed with T-DXd plus pertuzumab indicates a potential shift in the first-line treatment paradigm for previously untreated HER2-positive advanced or metastatic breast cancer. This raises new questions regarding optimal drug sequencing and maintenance strategies.”

The trial's outcomes could redefine treatment protocols for HER2-positive breast cancer, a group that historically has shown limited response to conventional therapies. The findings suggest that the combination of T-DXd with pertuzumab not only offers a statistically significant PFS but may also lead to changes in how oncologists approach both induction and maintenance therapies.

The DESTINY-Breast09 trial, registered under NCT04784715, demonstrated a hazard ratio of 0.56 (95% CI, 0.44-0.71; P < 0.00001), highlighting the robustness of the results. The trial design involved a random assignment of patients to three groups: the standard THP regimen, T-DXd alone, and T-DXd with pertuzumab, with PFS as the primary endpoint.

Amidst the promising results, several critical questions and considerations arise. Huppert noted the importance of understanding the potential for maintenance therapy following initial treatment with T-DXd. In her discussion, she proposed exploring whether the addition of a HER2-targeted tyrosine kinase inhibitor (TKI) or a PIK3CA inhibitor could enhance maintenance strategies.

Moreover, Dr. Huppert highlighted ongoing studies like the phase 3 PATINA trial (NCT02947685), which investigates the combination of palbociclib with anti-HER2 therapy for maintenance in hormone receptor-positive, HER2-positive metastatic breast cancer. Such trials are pivotal in determining how best to integrate novel agents into established regimens to optimize patient outcomes.

The implications of these data also extend to future treatment sequencing. Traditionally, THP has been followed by T-DXd; however, the introduction of T-DXd into the first-line setting raises questions about the position of THP in subsequent lines of therapy. As these protocols evolve, it is essential to assess how effectively these combinations work and which patients may benefit most from a specific regimen.

Experts, including Dr. Tolaney and Dr. Tarantino, have echoed Huppert's sentiments, pointing out the need for continued research into the sequencing of therapies and the potential impact on patient quality of life and survival rates. Dr. Tolaney stated, "If T-DXd becomes a standard of care in the first-line setting, we will need to explore how best to utilize THP and other treatments thereafter."

As the oncology field awaits further data on overall survival and the role of maintenance therapy, the results from DESTINY-Breast09 promise to reshape the future landscape of HER2-positive breast cancer treatment. The ongoing research and trials will be crucial in determining the optimal pathways for patients navigating this challenging diagnosis.

In conclusion, while the DESTINY-Breast09 trial presents promising findings, the oncology community must remain vigilant in addressing the questions raised and ensuring that treatment strategies are refined to provide the best possible outcomes for patients with HER2-positive breast cancer.