Enhertu Significantly Cuts Recurrence Rates For Women With High-Risk HER2-Positive Breast Cancer — The Practice-Changing DESTINY-Breast05 Trial

“DESTINY-Breast05 is a practice-changing trial,” Dr. Francisco Esteva, chief of breast medical oncology at Northwell Health in New York, tells SurvivorNet.

‘Practice-Changing’ Trial Data

DESTINY-Breast05 is a large phase 3 trial in women with HER2-positive early-stage breast cancer who had chemotherapy and targeted therapy prior to surgery — and still had cancer left over in the breast and lymph nodes after surgery. These patients are considered high-risk for cancer returning.

These are exactly the people doctors worry most about in their daily practice, the ones who did “everything right” and still have residual disease.

In the trial, more than 1,600 patients were randomly assigned to receive either:

• Enhertu (trastuzumab deruxtecan) every 3 weeks for up to 14 cycles
• T-DM1 (Kadcyla) every 3 weeks for up to 14 cycles

The key measure in this trial is invasive disease-free survival (IDFS), or the length of time patients are alive and free from cancer coming back in the breast, lymph nodes, or elsewhere in the body.

Here’s what DESTINY-Breast05 showed:

• Enhertu reduced the risk of invasive disease recurrence or death by 53% compared with standard treatment T-DM1.
• At 3 years, 92.4% of women on Enhertu were alive and free of invasive disease compared with 83.7% on T-DM1 — an almost 9% improvement.
• Disease-free survival (DFS), a very similar measure, improved by the same 53%.
• Enhertu reduced the risk of the cancer spreading to distant organs by 51%, and even cut the risk of brain metastases by about 36%, compared with T-DM1.

For patients, those numbers mean something very significant: with Enhertu, fewer women in this high-risk group are seeing their cancer come back in the first few years after surgery.

That’s why many experts are already calling these results practice-changing and predicting Enhertu will become the new standard in this setting.

The Safety Profile: What To Know

Overall, side effects with Enhertu in DESTINY-Breast05 were described as “manageable” and similar in severity to T-DM1, but with different patterns.

Serious side effects occurred in about 50% of patients on Enhertu and 52% on T-DM1, so the overall “intensity” of treatment was roughly comparable. Enhertu did have higher rates of nausea and low white blood cell counts (neutropenia) than T-DM1.

The most important unique risk with Enhertu is interstitial lung disease (ILD)/pneumonitis. In DESTINY-Breast05, about 9 to 10% of patients on Enhertu developed some form of lung disease, compared with about 1 to 2% on T-DM1. Most cases were mild (grade 1-2) and managed with drug interruption and steroids.

The potential lung disease that comes with this treatment requires a closer follow-up with your health care team. In that sense, you may need frequent computerized tomography (CT scan) of the thorax, which can add burden to your routine.

Dr. Maysa Abu-Khalaf, a medical oncologist at Thomas Jefferson University in Philadelphia, tells SurvivorNet that scans may be every 12 or so weeks.

“It’s a life-threatening toxicity that even with monitoring it can happen,” she explains.

This is why doctors using Enhertu pay extremely close attention to new coughs, shortness of breath, or unexplained fever and often order imaging early if there’s any concern.

For many patients, the reduction in recurrence risk outweighs this added risk, especially with careful monitoring, but it’s a real trade-off that needs to be discussed.

Who Should Be Treated With Enhertu?

For a woman that meets this study criteria after surgery with residual HER2-positive disease, the decision is no longer only one option. We’re now in an era of T-DM1 vs. ENHERTU — and the choice is individualized.

Doctors will think about and take the following aspects into consideration when offering Enhertu vs. the standard treatment:

• Risk level: DESTINY-Breast05 focused on high-risk patients (large tumors, multiple positive nodes, or significant residual disease). If you fit that profile, Enhertu is more likely to be favored.
• Age and life expectancy: Younger patients with decades of life ahead may benefit the most from the stronger recurrence protection Enhertu offers.
• Lung health and other co-morbidities: Pre-existing lung disease, prior radiation to the chest, or autoimmune conditions may make the risk of ILD more concerning.
• Tolerance for risk vs. benefit: Some patients want whatever treatment approach offers the best chance of keeping cancer away no matter the risk, while others prioritize minimizing side-effects, even if that means a slightly higher recurrence risk.
• Access and logistics: Enhertu and T-DM1 are both IV drugs, given every 3 weeks in specialized centers. Insurance coverage and availability can also influence daily choice.

“The results of Destiny05 were pretty exciting. I think that there are still questions also about how to incorporate this into practice and how to choose the right high-risk patients that they included in that trial,” Dr. Kristina Fanucci, a breast oncologist at Dana-Farber Cancer Institute in Boston, says.

Questions To Ask Your Doctor

• Does my cancer have the characteristics that make me a good candidate for Enhertu?
• How often would I be monitored on Enhertu?
• Is there any reason you would still favor T-DM1 in my case?
• Can I switch treatments if I decide to start Enhertu afterwards?
• If the standard treatment doesn’t work, can I try Enhertu?

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