{
  "abstract": "Introduction Neoadjuvant therapy is the standard of care for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Studies on first-generation antibody-drug conjugates, such as trastuzumab emtansine (T-DM1), showed equal or slightly lower efficacy than chemotherapy combined with dual HER2 blockade. Trastuzumab deruxtecan (T-DXd) is a next-generation conjugate approved for the treatment of metastatic HER2-positive and HER2-low BC, with greatly improved efficacy compared to T-DM1.Methods and analysis ARIADNE is an academic, international, open-label, randomised, comparative phase IIB trial. A total of 370 patients with non-metastatic HER2-positive BC and an indication for neoadjuvant therapy will be included and randomised 1:1 to receive either (1) docetaxel (or paclitaxel), carboplatin, trastuzumab (H) and pertuzumab (P) for three cycles or (2) T-DXd for three cycles. Further treatment is based on the intrinsic molecular subtype determined by the Prosigna assay: patients with HER2-enriched disease (estimated 60%) continue the same treatment for three more cycles. Patients with oestrogen receptor (ER)-positive and luminal (estimated 30%) disease receive H and P for three cycles, combined with letrozole and ribociclib for two cycles. Patients with ER-negative and luminal, basal-like or normal-like disease (estimated 10%) either continue the same treatment for three more cycles in the case of a radiologic complete response, or, in the case of no complete response, they receive four cycles of dose-dense epirubicin and cyclophosphamide. The primary endpoint of ARIADNE is locally assessed rate of pathologic complete response in the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined by a pathologist blinded to treatment assignment (intention-to-treat (ITT) analysis). Key secondary endpoints include time-to-event endpoints (event-free, recurrence-free, distant recurrence-free and overall survival), safety, health-related quality of life and translational studies.Ethics and dissemination The study has been approved by the Swedish Medical Products Agency (Läkemedelsverket), the Swedish Ethical Review Authority (Etikprövningsmyndigheten) and the Norwegian Ethics Committee for Clinical Trials on Medicinal Products and Medical Devices, as well as by the review boards at all participating centres. Applications for ethical approval in Belgium, the Netherlands and Italy are ongoing. We intend to publish the results of the study in a scientific journal. The study results will be submitted to the European Union (EU) database within 1 year after the end of the clinical trial (CT).Trial registration number EU CT registration number: 2022-501504-95-00; ClinicalTrials.gov identifier: NCT05900206.",
  "authors": [
    {
      "affiliations": [
        "Breast Center, Theme Cancer, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden",
        "Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Alexios Matikas"
    },
    {
      "affiliations": [
        "Department of Oncology, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Bjørn Naume"
    },
    {
      "affiliations": [
        "Department of General Medical Oncology and Multidisciplinary Breast Centre, University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Hans Wildiers"
    },
    {
      "affiliations": [
        "Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Gabe Sonke"
    },
    {
      "affiliations": [
        "Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova, Italy",
        "Oncologia 2, Istituto Oncologico Veneto IRCCS, Padova, Italy"
      ],
      "name": "Maria Vittoria Dieci"
    },
    {
      "affiliations": [
        "Department of Surgical Sciences, Uppsala University, Uppsala, Sweden",
        "Section for Breast Surgery, Uppsala University Hospital (Akademiska), Uppsala, Sweden"
      ],
      "name": "Andreas Karakatsanis"
    },
    {
      "affiliations": [
        "Department of diagnostics and intervention, oncology, Umeå University, Umeå, Sweden"
      ],
      "name": "Anne Andersson"
    },
    {
      "affiliations": [
        "Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden",
        "Department of Oncology, Södersjukhuset, Stockholm, Sweden"
      ],
      "name": "Elin Barnekow"
    },
    {
      "affiliations": [
        "Breast Center, Capio Saint Göran’s Hospital, Stockholm, Sweden"
      ],
      "name": "Luisa Edman Kessler"
    },
    {
      "affiliations": [
        "Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Department of Medicine and Oncology, Southern Älvsborg Hospital, Borås, Sweden"
      ],
      "name": "Zakaria Einbeigi"
    },
    {
      "affiliations": [
        "Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Skåne University Hospital, Lund University, Lund, Sweden"
      ],
      "name": "Fredrika Killander"
    },
    {
      "affiliations": [
        "Institution of Clinical Sciences, Department of Oncology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden"
      ],
      "name": "Barbro Linderholm"
    },
    {
      "affiliations": [
        "Department of Oncology, Uppsala University Hospital and department of Immunology, Genetics and Pathology Uppsala University, Uppsala, Sweden"
      ],
      "name": "Aglaia Schiza"
    },
    {
      "affiliations": [
        "Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden"
      ],
      "name": "Antonis Valachis"
    },
    {
      "affiliations": [
        "Department of Oncology, Mälarsjukhuset, Eskilstuna, Sweden"
      ],
      "name": "Andreas Nearchou"
    },
    {
      "affiliations": [
        "Department of Oncology, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Olav Engebraaten"
    },
    {
      "affiliations": [
        "Department of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway"
      ],
      "name": "Alina Porojnicu"
    },
    {
      "affiliations": [
        "Department of Oncology, Stavanger University Hospital, Stavanger, Norway"
      ],
      "name": "Mari Hiorth Soland"
    },
    {
      "affiliations": [
        "Department of Oncology, Nordland Hospital Trust, Bodø, Norway"
      ],
      "name": "Bård Mannsåker"
    },
    {
      "affiliations": [
        "Breast Cancer Unit, Cancer Clinic, University Hospital in Trondheim, Trondheim, Norway"
      ],
      "name": "Sunil X Raj"
    },
    {
      "affiliations": [
        "Department of Oncology, University Hospital of North Norway, Tromsø, Norway"
      ],
      "name": "Egil Støre Blix"
    },
    {
      "affiliations": [
        "Department of Oncology, Møre og Romsdal Hospital Trust, Alesund, Norway"
      ],
      "name": "Cecilie Soma Nordstrand"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy",
        "Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy"
      ],
      "name": "Matteo Lambertini"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy",
        "Oncology and Hematology-Oncology Department, University of Milan, Milan, Italy"
      ],
      "name": "Claudio Vernieri"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Ziekenhuis Aan de Stroom, Wilrijk, Belgium"
      ],
      "name": "Kevin Punie"
    },
    {
      "affiliations": [
        "Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium"
      ],
      "name": "Christos Sotiriou"
    },
    {
      "affiliations": [
        "Breast Center, Theme Cancer, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden",
        "Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Jonas Bergh"
    },
    {
      "affiliations": [
        "SOLTI Cancer Research Group, Barcelona, Spain",
        "Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain"
      ],
      "name": "Guillermo Villacampa"
    },
    {
      "affiliations": [
        "Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Athanasios Zouzos"
    },
    {
      "affiliations": [
        "Breast Center, Theme Cancer, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden"
      ],
      "name": "Mats Hellström"
    },
    {
      "affiliations": [
        "Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden",
        "Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Johan Hartman"
    },
    {
      "affiliations": [
        "Breast Center, Theme Cancer, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden",
        "Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Theodoros Foukakis"
    }
  ],
  "title": "Randomised trial of trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer: a study protocol of ARIADNE",
  "uid": "f0d4e001-2c04-53d9-9c47-8243aef71f09"
}