A randomized trial of trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer (ARIADNE)

BackgroundNeoadjuvant therapy is the standard of care for the treatment of HER2-positive breast cancer. Studies on first generation antibody-drug conjugates such as trastuzumab emtansine (T-DM1) showed equal or slightly lesser 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 breast cancer, with greatly improved efficacy compared to T-DM1.Trial designARIADNE is an academic, international, open label, randomized, comparative phase IIB trial, conducted in Sweden and in Norway. A total of 370 patients with non-metastatic HER2-positive breast cancer and an indication for neoadjuvant therapy will be included and randomized 1:1 to receive either i) a taxane, carboplatin, trastuzumab and pertuzumab for three cycles or ii) T-DXd for three cycles. Further treatment is based on the intrinsic molecular subtype determined in a pretreatment biopsy by the Prosigna® assay: HER2-enriched (approx 65%) patients continue with the same treatment for three more cycles. Estrogen receptor (ER) positive and luminal (approx 25%) patients receive trastuzumab and pertuzumab for three cycles, combined with letrozole and ribociclib for two cycles. ER-negative and luminal or basal-like (approx 10%) patients either continue with the same treatment for three more cycles in case of radiologic complete response, or in 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 (pCR) at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined by a pathologist blinded to treatment assignment (intention-to-treat analysis). Key secondary endpoints are rates of complete radiologic response at three cycles; rates of pCR at the other two molecular groups and the two groups of the initial randomization; and event-free survival, defined as the time from randomization to disease progression, locoregional or distant recurrence, contralateral BC, or death due to any cause. First patient was randomized on 26th October 2023.Clinical trial identificationEU CT: 2022-501504-95-00; NCT05900206.Legal entity responsible for the studyKarolinska University Hospital, Stockholm, Sweden.FundingSwedish Research Council, AstraZeneca, Novartis, Veracyte.DisclosureT. Foukakis: Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer; Financial Interests, Institutional, Coordinating PI, Clinical trial support (research grant and study drug): AstraZeneca; Financial Interests, Institutional, Coordinating PI, Clinical trial support (research grant and study drug): Novartis; Financial Interests, Institutional, Coordinating PI, Discount on the Prosigna PAM50 assay in ARIADNE clinical trial: Veracyte. A. Valachis: Financial Interests, Institutional, Research Grant, Research Grant for a research project on Molecular profiling of triple negative breast cancer: Roche; Financial Interests, Institutional, Coordinating PI, PRODAT trial: Novartis; Financial Interests, Institutional, Coordinating PI, CHECKMATE-401 trial: Bristol-Myers-Squibb; Financial Interests, Institutional, Coordinating PI, CHECKMATE-76K trial: Bristol-Myers-Squibb; Financial Interests, Institutional, Coordinating PI, TELEPIK trial: Novartis; Financial Interests, Institutional, Coordinating PI, DESTINY-Breast09 trial: AstraZeneca; Financial Interests, Institutional, Research Grant: MSD. J. Bergh: Other, Fees (honoraria) to Coronis and Asklepios Cancer Research AB as an invited speaker/chair from AstraZeneca and Roche, respectively.: Coronis and Asklepios Cancer Research AB.; Other, Institutional honoraria as chapter co-author for UpToDate to Asklepios Medicin HB. Co-author on a chapter on �Prognostic and Predictive factors in early, non-metastatic breast cancer�.: Asklepios Medicin; Other, Institutional research grants received mote than ten years ago to Karolinska Institutet and/or University Hospital for molecular marker studies/ clinical studies (we are still working with the material). No personal payments for these activities.: Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche and Sanofi-Aventis; Other, Stocks in Stratipath AB. The company is involved in AI based diagnostics for breast cancer.: Stratipath AB. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. J. Hartman: Financial Interests, Personal, Ownership Interest: Stratipath. A. Matikas: Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Coordinating PI, International co-PI of academic trial ARIADNE (EU CT: 2022-501504-95-00): AstraZeneca, Novartis, Veracyte; Financial Interests, Institutional, Coordinating PI, Registry study: Merck; Non-Financial Interests, Advisory Role: Veracyte, Roche. All other authors have declared no conflicts of interest.