Randomised trial of trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer: a study protocol of ARIADNE

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.