The combination of trastuzumab deruxtecan with pertuzumab can delay cancer growth for longer than the current standard of care in people with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer, according to data from the phase 3 DESTINY-Breast09 clinical trial, presented By Dr Sara Tolaney at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

The current first-line treatment for people with locally advanced or metastatic HER2-positive breast cancer is a taxane given in combination with the HER2-targeted therapy drugs trastuzumab and pertuzumab.

This treatment is known as THP and has been the standard of care for more than 20 years. However, most patients who receive THP experience cancer growth within 2 years of treatment.

Trastuzumab deruxtecan (Enhertu) is a type of HER2-targeted therapy called an antibody-drug conjugate that is made up of trastuzumab attached to deruxtecan, a chemotherapy drug. Trastuzumab deruxtecan has shown promise as a treatment for metastatic breast cancer that has progressed after earlier treatments no longer work. In the DESTINY-Breast09 clinical trial, researchers wanted to learn if trastuzumab deruxtecan could also improve outcomes for patients in the first-line setting.

The study included 1,157 patients with HER2-positive locally advanced or metastatic breast cancer who had not received treatment with chemotherapy or HER2-targeted therapy.

The patients were randomly assigned to receive either trastuzumab deruxtecan with a placebo (387 patients), trastuzumab deruxtecan with pertuzumab (383 patients), or THP (387 patients). However, at the time of this initial analysis, the researchers are presenting data only from the trastuzumab deruxtecan with pertuzumab group and the THP group.

Among the patients in these two groups, 52% had de novo disease where the cancer had already spread to other parts of the body at the time of diagnosis, 54% had hormone receptor (HR)-positive cancer, and 48% had disease that recurred after treatment in the early-stage setting. About half the patients in both groups were from Asia, and most patients were younger than 65.

Key Findings

At a median follow-up of nearly 2.5 years (29 months), the study found that:

• Trastuzumab deruxtecan with pertuzumab reduced the risk of disease progression or death by 44% for patients.
• The median progression-free survival (PFS) was over 3 years in the trastuzumab deruxtecan with pertuzumab group (40.7 months). In the THP group, the median PFS was slightly over 2 years (26.9 months). This benefit was seen across all subgroups.
• At 2 years, about 70% of patients in the trastuzumab deruxtecan with pertuzumab group had not seen their cancer grow or spread, compared to about 52% in the THP group.
• For the patients who received trastuzumab deruxtecan and pertuzumab, about 85% had their cancer shrink or disappear compared to 78.6% of those in the THP group. About 15% of patients who responded to treatment with trastuzumab deruxtecan and pertuzumab had no signs of cancer in response to the treatment vs. 8.5% in the THP group.
• The analysis of overall survival is immature, but researchers observed a trend in improvement in overall survival for those in the trastuzumab deruxtecan with pertuzumab group. The researchers will continue to follow patients to better assess longer-term overall survival data.

Both groups experienced similar rates of serious side effects. However, the length of treatment was longer in the trastuzumab deruxtecan group, and certain side effects, including nausea, vomiting, and constipation, were more common in this group. Interstitial lung disease, a known side effect of trastuzumab deruxtecan, occurred in about 12% of patients in this group. However, most of these cases were not severe.

“The DESTINY-Breast09 trial has the potential to establish a new first line standard of care for metastatic HER2-positive breast cancer, a setting which hasn’t seen significant innovation in more than a decade. Trastuzumab deruxtecan represents a highly effective targeted therapy and has demonstrated promising outcomes in both the front-line and late-line HER2-positive metastatic breast cancer settings,” said lead study author Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts.

“The findings from Destiny-Breast09 represent a new first line standard treatment option for HER-2 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,” said Rebecca Dent, MD, MSc, Deputy Chief Executive Officer (Clinical) at National Cancer Center Singapore and an ASCO Expert in breast cancer.

The study will continue until a final PFS analysis is done and until final overall survival is reported.

Watch the related interview here.

Source: ASCO