DESTINY-Breast09 Demonstrates First-Line Superiority of Enhertu Plus Pertuzumab in HER2-Positive Metastatic Breast Cancer

Enhertu (trastuzumab deruxtecan) combined with pertuzumab has shown a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) over the current standard-of-care regimen of taxane, trastuzumab, and pertuzumab (THP) in patients with HER2-positive metastatic breast cancer, according to topline results from the phase III DESTINY-Breast09 trial. The study is the first in more than 10 years to demonstrate superiority over THP across a broad patient population in the first-line setting.

Conducted globally among 1,157 patients, DESTINY-Breast09 is a randomized, open-label trial evaluating trastuzumab deruxtecan either as monotherapy or in combination with pertuzumab versus THP in the first-line setting. In this planned interim analysis, the trastuzumab deruxtecan-plus-pertuzumab arm met its primary end point, achieving a statistically significant PFS benefit across all prespecified patient subgroups. Although overall survival data were immature at the time of analysis, interim findings revealed a favorable trend for the trastuzumab deruxtecan combination. The comparative arm of trastuzumab deruxtecan monotherapy versus THP remains ongoing and blinded.

“This is the first trial in more than a decade to demonstrate superior efficacy across a broad HER2-positive metastatic breast cancer patient population compared to the current 1st-line standard of care,” said Susan Galbraith, executive vice president, Oncology Haematology R&D at AstraZeneca. “This is a significant milestone for patients and sets the foundation for Enhertu in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting.”

Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, emphasized the relevance of earlier intervention, stating that “these new findings suggest that starting treatment with Enhertu in combination with pertuzumab at the time of metastatic diagnosis delays disease progression, postponing the time until additional treatment may be needed.”

HER2-positive metastatic breast cancer is marked by aggressive disease biology, affecting approximately 15% to 20% of patients with metastatic breast cancer. Despite advancements in HER2-targeted therapies, disease progression remains a critical issue, with most patients experiencing progression within 2 years of first-line THP therapy. Nearly one-third of patients never proceed to second-line treatment due to rapid disease progression or death.

The safety profile of the trastuzumab deruxtecan and pertuzumab combination was consistent with what is already known for each individual agent.

Trastuzumab deruxtecan is already approved in more than 75 countries as a second-line therapy based on results from DESTINY-Breast03. The DESTINY-Breast09 findings may expand the utility of trastuzumab deruxtecan into the first-line setting.

Reference

Enhertu plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival vs. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. April 21, 2025. Accessed April 21, 2025.https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-combination-improved-pfs-in-1l-her-positive-mbc.html