What The Approval Of Enhertu + Pertuzumab Means — Your Colleagues On How The Combination Will Change Practice

The FDA approval of trastuzumab deruxtecan (Enhertu) combined with pertuzumab (Perjeta) is expected to change clinical practice when it comes to treating HER2-positive metastatic breast cancer, according to an experienced breast oncologists who spoke to SurvivorNet.

The U.S. Food and Drug Administration authorized the use of Enhertu combined with pertuzumab, on December 15, 2025, as a main form of therapy for patients with HER2-positive breast cancer that has spread and cannot be treated surgically.

Our experts say this approval enables physicians to offer more targeted, patient-specific, and less chemotherapy-intensive options; however, it also requires careful monitoring of side effects and adjustments to treatment plans.

Results from the Phase 3 DESTINY-Breast09 trial revealed that patients treated with the combination of Enhertu and pertuzumab experienced a much longer period before their cancer progressed compared with those receiving the previous standard first-line regimen.

The study found that the new drug combination lowered the risk of disease worsening or death by approximately 44%, with a median progression-free period exceeding three years.

Following the approval, Dr. Francisco Esteva, an Oncology Specialist in New York, told SurvivorNet, “To me, DESTINY-Breast05 is a practice-changing trial. I will use ENHERTU in HER2 patients with residual disease after taxane and HP type of therapy.”

The study compared Trastuzumab deruxtecan (T-DXd) with Trastuzumab emtansine (T-DM1) in high-risk HER2-positive patients who still had invasive cancer after pre-surgery therapy. Patients treated with T-DXd experienced a 9% higher rate of remaining free from cancer recurrence compared to those receiving T-DM1.

Dr. Esteva continued, “The serious ILD [interstitial lung disease], is less than one percent, but a nine percent improvement in disease-free survival in absolute numbers, not relative, is a significant improvement.

“So for women at very high risk who present with or have positive nodes after neoadjuvant therapy, this would be my go-to. But it is hard to give this full treatment. People get tired and so on, and only about 70% of patients actually made it to the full fourteen cycles.”

Potential Side Effects

Meanwhile, Dr. Kristina Fanucci, a breast medical oncologist at Dana-Farber Cancer Institute, understands the new combination shows a notable benefit, however, she remains careful about the potential side effects that may arise.

“I also have concerns about the increased side effects that come along with that regimen,” she explained.

Here’s a summary of the more serious potential side effects, including a black box warning associated with the newly approved drug:

• Lung Disease/Pneumonitis (Boxed Warning)
• Embryo-Fetal Harm When Administered To Pregnant Women (Boxed Warning)
• Heart Failure
• Lower White Blood Cell Counts

ENHERTU Side Effects (Mild to Severe): Potential side effects include G.I. symptoms (such as nausea, vomiting, diarrhea, and loss of appetite), fatigue, fever, and hairloss.

‘Practice-Changing for Selected Patients’

As for Dr. Heather McArthur, the Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Cancer Research at University of Texas Southwestern (UTSW) Medical Center, she believes the drug is “practice-changing for selected patients.”

She described the approval as a new approach for doctors compared to existing adjuvant therapies.

“They have a lot of work ahead of them in terms of educating our colleagues around who actually is appropriate, how often to scan, and how to manage this differently than we’re used to in the adjuvant setting,” Dr. McArthur said.

“What I would love to see as a next step is a shorter duration of treatment. Fourteen cycles is a lot of treatment for people who’ve already had a lot of therapy, and it’s a very arbitrary number.”

Dr. Amy Comander, Director of Breast Oncology and Survivorship at Mass General Brigham Cancer Institute, also addressed her excitement for this new development.

“In this study, it was shown that the antibody-drug conjugate plus pertuzumab pushed median progression free survival to ~40.7 months, far outpacing the 26.9 months achieved with a standard taxane, trastuzumab, and pertuzumab regimen,” Dr. Comander said.

“The result signals a decisive shift away from chemotherapy-anchored care toward ADC (Antibody-Drug Conjugate therapy)-based strategies, ushering in a new era for patients with HER2-positive disease.

On the other hand, Dr. Kevin Punie, of University Hospitals Leuven, Gasthuisberg, Belgium, says that giving this drug combination continuously until the cancer progresses may not be necessary for all patients.

Dr. Punia points out that, for some, a shorter initial course of 12–18 weeks followed by a maintenance therapy could achieve similar results while helping to minimize side effects and reduce the overall treatment burden, improving quality of life.

He expects that in practice, the treatment will often be followed by maintenance therapy, similar to what was done in the phase III AFT-38 PATINA trial, presented at the 2024 San Antonio Breast Cancer Symposium. In that study, patients with hormone receptor–positive breast cancer received a combination of endocrine therapy, trastuzumab, pertuzumab, and palbociclib as maintenance after initial treatment.

Dr. Punie concluded, “While we have seen very recently at SABCS also data on the HER-2-Climb of five study really pointing towards slight benefit of maintenance therapy with TU Carib and trastuzumab in patients who are HR negative.

“So I certainly think that we will more evolve into a little bit of a hybrid situation where the best elements of all clinical trials are being a little bit all put together and then patient per patient there will be some differences, but it’s good to have this option, but it does not require necessarily that all patients will be received TVX exam until progression in first line metastatic her with positive breast cancer.”