- Results from interim analysis of the international, multicenter, randomized phase III DESTINY-Breast09 study show that the combination of trastuzumab dertuxtecan plus pertuzumab significantly improved progression-free survival and reduced the risk of disease progression or death in 44% of patients with no prior therapy for HER2-positive metastatic breast cancer.
- Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) specifically designed to target HER2 and is approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a second-line standard of care for some indications.
- Published today in The New England Journal of Medicine, results from this study show the potential of trastuzumab dertuxtecan combined with pertuzumab to become a new standard first-line treatment for these patients.
- Led at the European level by the SOLTI academic and cooperative breast cancer clinical research group, the TOP-REAL trial, envisaged to start later this year, will give the opportunity to patients who meet the criteria for this new first-line indication, while pending approval by the EMA and funding through the Spanish National Health System.
Results from interim analysis of the international, multicenter, randomized (phase III DESTINY-Breast09 study, co-authored by Cristina Saura, Head of the Vall d’Hebron University Hospital’s Breast Cancer Unit and the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group, demonstrate that the investigational combination of antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) plus monoclonal antibody pertuzumab improved progression-free survival (PFS) in patients with HER2-positive (HER2+) metastatic breast cancer who had not previously received other HER2-directed therapy or chemotherapy in the context of advanced disease.
DESTINY-Breast09 is the first trial in more than a decade to show an improvement in outcomes in the first-line setting compared to standard of care in patients with previously untreated HER2+ metastatic breast cancer, results of which published today in The New England Journal of Medicine*.
Approximately one in five patients diagnosed with breast cancer worldwide will have HER2+ breast cancer, a particularly aggressive form of the disease primarily due to the overexpression of the HER2 protein, which can lead to accelerated tumor growth, disease progression, and a challenging prognosis.
“In recent years, new therapies targeting HER2 have radically improved treatment outcomes for these patients,” said Cristina Saura, a member of the DESTINY-Breast09 steering committee. “However, patients with HER2-positive metastatic breast cancer can often experience disease progression at around two years following standard-of-care first-line treatment, and cases diagnosed at an advanced stage are challenging to treat successfully, underscoring a current unmet need for more efficacious therapeutic strategies and treatment combinations.”
Findings from this present study, first reported at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, show a median PFS of 40.7 months with trastuzumab deruxtecan plus pertuzumab compared to 26.9 months for standard-of-care. The investigational combination reduced the risk of disease progression or death by 44%.
Confirmed objective response rate (ORR) with the trastuzumab deruxtecan/pertuzumab combination was 85.1%, with a median duration of response that exceeded three years (39.2 months) versus 26.4 months with standard first-line therapy.
“These results reinforce the importance of offering optimal HER2-targeted approaches to patients with HER2+ metastatic breast cancer as first-line therapy to better control the disease from the outset,”added Saura. “Our findings indicate that the combination of trastuzumab deruxtecan with pertuzumab from the time of diagnosis could delay disease progression, postponing the need for a second line of treatment.”
Led at the European level by the SOLTI breast cancer clinical research group, the TOP-REAL clinical trial has been designed to tackle one of the major challenges associated with this new treatment strategy: toxicity control. This study incorporates pioneering digital tools (Resilience and CANKADO) for the early detection and management of potential side effects, enabling the real-time monitoring of patients’ well-being to improve their quality of life during treatment.
“TOP-REAL will address key questions that were left unanswered in the DESTINY-Breast09 study. This new study is highly relevant on a practical level. On the one hand, we will generate additional scientific evidence on how to improve patients’ quality of life with this new treatment. This study will also enable us to offer early and timely access to this first line treatment while funding is in the process of authorization by the healthcare system for this new indication, since we know that this can take an average of about two years in Spain,” added Cristina Saura, Principal Investigator of this study and a member of SOLTI’s Board of Directors.
This study is being conducted in coordination with other similar research groups internationally, specifically the UNICANCER (France) and WSG (Germany) groups, as a key collaboration to expand patient access to novel therapies and further strengthen the scientific relevance of the findings. Promoted by SOLTI, the launch of TOP-REAL has been possible thanks to CHORUS, an initiative of the Daiichi Sankyo-AstraZeneca alliance, with VHIO as the Spanish representative. The aim is to promote new proposals for clinical and academic studies to provide earlier access to innovative treatments.
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Reference
* Sara M. Tolaney, M.D.1, Zefei Jiang, M.D.2, Qingyuan Zhang, M.D.3, Romualdo Barroso-Sousa, M.D.4, Yeon Hee Park, M.D.5, Mothaffar F. Rimawi, M.D.6, Cristina Saura, M.D.7, Andreas Schneeweiss, M.D.8, Masakazu Toi, M.D.9, Yee Soo Chae, M.D.10, Yasemin Kemal, M.D.11, Mukesh Chaudhari, M.D.12, Mehmet A.N. Şendur, M.D.13, Toshinari Yamashita, M.D.14, Monica Casalnuovo, M.D.15, Michael A. Danso, M.D.16, Jie Liu, Ph.D.17, Jagdish Shetty, M.D.18, Pia Herbolsheimer, M.D.18, Sibylle Loibl, M.D.19 on behalf of the DESTINY-Breast09 Trial Investigators.Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. Published October 29, 2025. DOI: 10.1056/NEJMoa2508668
