The European Medicines Agency issued a positive opinion on July 23, 2026, for trastuzumab deruxtecan combined with pertuzumab as a first-line treatment for adults with unresectable or metastatic HER2-positive breast cancer, doctors at the Alexandra Hospital's Therapeutic Clinic at the National and Kapodistrian University of Athens Medical School said.
Dr. Maria Kaparelou, a pathologist and oncologist, and Thanos Dimopoulos, professor of therapeutics, oncology and haematology and director of the Therapeutic Clinic at Alexandra Hospital and a former rector of the university, said two recent developments show how the treatment approach for advanced breast cancer keeps evolving.
Breast cancer is the most common cancer in women and shows significant molecular and biological diversity. Hormone receptor status, HER2 overexpression or amplification, and a wide range of molecular biomarkers now guide treatment choices. Targeted therapies, antibody-drug conjugates and CDK4/6 inhibitors have substantially changed the course of metastatic disease in recent years.
New standard for HER2-positive metastatic breast cancer
The EMA's recommendation is based on the randomised phase III DESTINY-Breast09 trial, which compared trastuzumab deruxtecan plus pertuzumab against the previously established first-line regimen of taxane, trastuzumab and pertuzumab, known as THP.
Trastuzumab deruxtecan is an antibody-drug conjugate that pairs a monoclonal antibody targeting HER2 with a potent topoisomerase I inhibitor, allowing the cytotoxic payload to be delivered selectively to HER2-expressing cancer cells.
The trial results were notable. Median progression-free survival reached 40.7 months with trastuzumab deruxtecan and pertuzumab, compared with 26.9 months with THP, a 44% reduction in the relative risk of disease progression or death. The objective response rate was 85.1% versus 78.6%, with complete responses recorded in 15.1% and 8.5% of patients respectively. Median duration of response was 39.2 months with the new combination versus 26.4 months with the established therapy.
Monitoring for interstitial lung disease and pneumonitis, a known side effect of trastuzumab deruxtecan, remains important. In the trial, treatment-related interstitial lung disease or pneumonitis occurred in 12.1% of patients who received trastuzumab deruxtecan and pertuzumab. Most cases were grade 1 to 2, though there were two fatal events.
The data could lead to a substantial shift in first-line treatment for HER2-positive metastatic breast cancer, moving a highly effective antibody-drug conjugate into an earlier stage of care.
CDK4/6 inhibition in visceral crisis
A second significant development concerns one of the most difficult clinical situations in HR-positive, HER2-negative advanced breast cancer: visceral crisis, a state of severe organ dysfunction caused by rapidly progressing disease, in which chemotherapy has traditionally been the preferred option because a fast response is needed.
The multicentre, non-randomised phase II DARVIN trial examined whether the CDK4/6 inhibitor dalpiciclib, combined with endocrine therapy, could offer an effective alternative for women with HR-positive, HER2-negative advanced breast cancer experiencing visceral crisis. The trial enrolled 53 patients in total.
The primary endpoint was met, with 92.5% of patients alive at six months. Progression-free survival was 11.2 months, the objective response rate was 26.4% and the disease control rate was 79.2%. Median overall survival had not yet been reached at the time of the analysis.
Haematological toxicity was significant, with grade 3 or higher neutropenia in 77.4% of patients and grade 3 or higher leukopenia in 54.7%.
The doctors said the results need careful interpretation, since the trial was small, single-arm and non-randomised, and therefore do not yet establish a case for replacing chemotherapy as the standard approach to visceral crisis. Still, they said the findings represent an important clinical signal that endocrine therapy combined with CDK4/6 inhibition may have a role even in selected patients with a high disease burden and rapidly progressing illness.
Together, the two developments reflect the current direction of advanced breast cancer treatment: stronger biological targeting, reduced reliance on conventional chemotherapy, and treatment strategies tailored to a patient's molecular subtype and the specific features of their disease.
