Understanding the Importance of the DESTINY-Breast09 Trial in HER2+ Breast Cancer

Dr. Sara M. Tolaney discusses key takeaways from the DESTINY-Breast09 trial that patients with HER2+ advanced or metastatic breast cancer should know.

Treatment with first-line Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) plus Perjeta (pertuzumab) demonstrated improvements in key survival outcomes compared with the standard care for those with HER2-positive advanced or metastatic breast cancer, Dr. Sara M. Tolaney emphasized in an interview with CURE, potentially shifting the way this patient population will be treated in the future.

These data were garnered from the phase 3 DESTINY-Breast09 trial which was presented at the 2025 ASCO Annual Meeting.

“The combination of [Enhertu] and Perjeta, as we saw in DESTINY-Breast09, really doubled progression-free survival [for patients]. Therefore, I think [this treatment] does present a really nice new potential first-line therapy option for patients if they're newly diagnosed with metastatic HER2-positive positive breast cancer,” Tolaney explained.

In the interview, she delved into detail on the outcomes of the DESTINY-Breast09 trial, the treatment's safety profile, and what this means for patients with HER2-positive breast cancer.

Tolaney is a senior physician at Dana-Farber Cancer Institute and the chief of the Division of Breast Oncology at the Susan F. Smith Center for Women's Cancers, where she also serves as the associate director. Additionally, she is an associate professor of medicine at Harvard Medical School, located in Boston, Massachusetts.

CURE: What should patients with breast cancer know about the DESTINY-Breast09 trial in regard to background and enrollment information?

Tolaney: Thanks. We know about 15% to 20% of all breast cancers are HER2-positive, and outcomes for patients with metastatic HER2-positive disease have dramatically evolved over the past few years. This improvement is largely due to the introduction of trastuzumab deruxtecan, also known as T-DXd and Enhertu.

Enhertu is an antibody-drug conjugate that delivers chemotherapy in a targeted fashion directly into HER2-positive cancer cells. It is currently approved as a second-line standard of care for patients with metastatic HER2-positive breast cancer, primarily based on data from the DESTINY-Breast03 study. This study demonstrated unprecedented outcomes, controlling cancer for almost 29 months with the use of Enhertu.

Consequently, there's been significant interest in moving Enhertu from the second-line setting to the first-line. The current first-line standard of care is a taxane plus Herceptin (trastuzumab) and Perjeta, or THP, which is associated with a progression-free survival of a little under 19 months. The prevailing thought was that since Enhertu is performing so well, it would likely be a better choice than our current first-line standard of care. Therefore, the DESTINY-Breast09 study was specifically designed to answer whether Enhertu should be the first treatment patients receive if they have metastatic HER2-positive breast cancer.

What new data were shared on the DESTINY-Breast09 trial at the ASCO Annual Meeting? What do the new findings mean for patients?

The DESTINY-Breast09 study was a randomized phase 3 trial that enrolled patients with HER2-positive metastatic disease who had not received any prior systemic therapy in the metastatic setting. These patients were randomized into three arms: Enhertu alone, Enhertu with Perjeta, or the standard first-line treatment of a taxane with Herceptin and Perjeta (THP). The study was specifically designed to determine if the Enhertu arms were superior to the current standard of care.

What was presented at ASCO was data from an interim analysis comparing Enhertu and Perjeta to THP. This comparison met the predefined criteria for success at the time of the interim analysis. In contrast, the Enhertu alone arm did not meet the stringent threshold set for success at this very early time point. Consequently, the Enhertu alone arm remains blinded, and patients continue to be followed. We anticipate seeing those data in a future presentation.

However, at ASCO, we presented the comparison of Enhertu with Perjeta to THP, and found that, in essence, the combination of Enhertu and Perjeta almost doubled progression-free survival. This means it allowed cancer to be controlled for nearly twice as long as in the control arm. Specifically, the progression-free survival for the Enhertu and Perjeta arm was 40.7 months, compared to 26.9 months for THP. As you can see, this represents a substantial difference between the two arms, almost a 14-month improvement.

Given these very significant improvements in progression-free survival, I believe Enhertu and Perjeta could be a new potential first-line treatment option for patients with metastatic HER2-positive breast cancer.

How soon might this new combination be available in clinical practice, and what steps should a patient take if they are interested in discussing it with their care team?

We will have to await FDA approval for this regimen. The data will be submitted to regulatory authorities, and we'll then await their decision. We also hope to see future changes in the National Comprehensive Cancer Network (NCCN) Guidelines.

Certainly, patients can discuss this data with their physicians. Enhertu is an approved drug, though currently for the second-line setting. So, it remains to be seen if insurance providers would cover Enhertu and Perjeta in the first-line setting even before official approval. Sometimes, this happens given how robust the data is, but it's definitely something you can discuss with your physician.

What should patients know about the potential side effects of Enhertu and Perjeta, such as nausea, fatigue, or low white blood cell counts, and how are these managed in practice?

The toxicities observed in the DESTINY-Breast09 study with Enhertu and Perjeta were largely consistent with the known side effects of these drugs. Common toxicities included nausea, diarrhea, and neutropenia.

A notable concern was interstitial lung disease (ILD), or inflammation of the lungs, which developed in about 12% of patients in the Enhertu and Perjeta arm. While predominantly low-grade inflammatory changes, there were unfortunately two deaths attributed to ILD in the trial.

Therefore, it's crucial for patients receiving Enhertu and Perjeta to receive prophylactic therapy to prevent nausea, which typically works very well. I usually recommend three different medications to help prevent nausea with Enhertu. It's also vital to monitor patients for any changes in their lungs or symptoms that could suggest lung inflammation. Patients should be aware of ILD as a potential toxicity and should promptly inform their physician if they develop any related symptoms.

The study showed benefit across subgroups. Why is this important for patients who may not respond as well to other treatments?

We know that certain features of HER2-positive cancer can sometimes suggest that patients may not respond as well to therapy. For example, if a patient has a PI3 kinase mutation, which is present in about 30% of those with HER2-positive disease, their duration on a given treatment is often shorter than for someone without this mutation.

Interestingly, in the DESTINY-Breast09 study, we observed that the benefit of Enhertu and Perjeta was seen irrespective of mutational status. This is excellent news. Furthermore, the benefits were also observed irrespective of hormone receptor status, meaning we saw positive outcomes across all patient subsets. This broad applicability is truly important for patients.

How might this study change the treatment landscape moving forward?

The combination of Enhertu and Perjeta, as we saw in DESTINY-Breast09, really doubled progression-free survival for patients. Therefore, I think this does present a really nice new potential first-line therapy option for patients if they're newly diagnosed with metastatic HER2-positive positive breast cancer.

Transcript has been edited for clarity and conciseness.

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