339TiP - A randomized trial of trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer (ARIADNE)

Background

Neoadjuvant 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 design

ARIADNE 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 26^th October 2023.

Clinical trial identification

EU CT: 2022-501504-95-00; NCT05900206.

Editorial acknowledgement

Legal entity responsible for the study

Karolinska University Hospital, Stockholm, Sweden.

Funding

Swedish Research Council, AstraZeneca, Novartis, Veracyte.

Disclosure

T. 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.