T-DXd Plus Pertuzumab Improves PFS Over THP in HER2+ Metastatic Breast Cancer

The safety profile of the combination was consistent with labels of the respective drugs.

Treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab led to a significant improvement in progression-free survival (PFS) compared with standard taxane plus trastuzumab and pertuzumab (THP) therapy in the frontline treatment of patients with HER2-positive metastatic breast cancer, according to interim results from the phase 3 DESTINY-Breast09 trial (NCT04784715).¹

The PFS benefit with T-DXd was observed across all prespecified patient subgroups. Overall survival (OS) data were not mature at the time of the analysis; however, they trended toward favoring T-DXd plus pertuzumab over THP.

“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 first-line standard of care,” Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, stated in a news release. “This is a significant milestone for patients and sets the foundation for [T-DXd] in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting.”

The safety profile of T-DXd plus pertuzumab was consistent with the known safety profiles of the individual therapies, according to the news release.

Data from the portion of the trial evaluating T-DXd plus pertuzumab are planned to be presented at a future medical meeting and will also be shared with regulatory authorities.

The portion of the trial evaluating T-DXd monotherapy vs THP is still blinded to patients, and trial investigators plan to continue this part of the study to the final PFS analysis.

“The results from DESTINY-Breast09 reinforce the importance of effectively targeting HER2 to achieve durable disease control early in the treatment of [patients with] HER2-positive metastatic breast cancer,” Ken Takeshita, Global Head of R&D at Daiichi Sankyo, added in the news release. “Building on the positive results seen with [T-DXd] in the second-line setting, these new findings suggest that starting treatment with [T-DXd] in combination with pertuzumab at the time of metastatic diagnosis delays disease progression, postponing the time until additional treatment may be needed.”

Diving Into the DESTINY-Breast09 Design

The global, multicenter, open-label DESTINY-Breast09 trial enrolled 1157 patients across several sites in Africa, Asia, Europe, North America, and South America. Patients needed to be at least 18 years of age and have pathologically documented breast cancer that was advanced or metastatic, locally assessed and prospectively centrally confirmed as HER2-positive per immunohistochemistry or in situ hybridization, and hormone receptor (HR)–positive or HR-negative in the metastatic setting per local testing.² Patients could not have received prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer; 1 prior line of endocrine therapy in the metastatic setting was permitted. However, patients who had received chemotherapy or HER2-targeted therapy in the neoadjuvant or adjuvant setting were eligible if more than 6 months had elapsed from treatment to metastatic disease diagnosis. Patients also needed to have protocol-defined adequate organ and bone marrow function, as well as an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1:1 to receive T-DXd monotherapy, T-DXd plus pertuzumab, or THP consisting of a taxane (either docetaxel or paclitaxel) plus trastuzumab and pertuzumab. Patients were stratified by prior treatment (de novo metastatic disease vs progression from early-stage disease), HR status, and PIK3CA mutation status.

The primary end point is PFS per blinded independent central review in both the T-DXd monotherapy and combination arms. Key secondary end points are investigator-assessed PFS, OS, overall response rate, duration of response, investigator-assessed time to second progression or death, patient-reported tolerability, pharmacokinetics, and safety.

References

1. 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
2. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated December 16, 2024. Accessed April 21, 2025. https://clinicaltrials.gov/study/NCT04784715