Matikas Alexios, Naume Bjørn, Wildiers Hans, Sonke Gabe, Dieci Maria Vittoria, Karakatsanis Andreas, Andersson Anne, Barnekow Elin, Kessler Luisa Edman, Einbeigi Zakaria, Killander Fredrika, Linderholm Barbro, Schiza Aglaia, Valachis Antonis, Nearchou Andreas, Engebraaten Olav, Porojnicu Alina, Soland Mari Hiorth, Mannsåker Bård, Raj Sunil X, Blix Egil Støre, Nordstrand Cecilie Soma, Lambertini Matteo, Vernieri Claudio, Punie Kevin, Sotiriou Christos, Bergh Jonas, Villacampa Guillermo, Zouzos Athanasios, Hellström Mats, Hartman Johan, Foukakis Theodoros
Breast Center, Theme Cancer, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden.
BMJ Open. 2025 Aug 27;15(8):e102626. doi: 10.1136/bmjopen-2025-102626.
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.
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.
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).
EU CT registration number: 2022-501504-95-00; ClinicalTrials.gov identifier: NCT05900206.
新辅助治疗是治疗人表皮生长因子受体2（HER2）阳性乳腺癌（BC）的标准治疗方法。对第一代抗体药物偶联物（如曲妥珠单抗恩美曲妥珠单抗（T-DM1））的研究表明，其疗效与化疗联合双重HER2阻断相当或略低。曲妥珠单抗德曲妥珠单抗（T-DXd）是一种新一代偶联物，已被批准用于治疗转移性HER2阳性和HER2低表达BC，与T-DM1相比疗效有显著提高。
ARIADNE是一项学术性、国际性、开放标签、随机、对照的IIB期试验。总共将纳入370例非转移性HER2阳性BC且有新辅助治疗指征的患者，并按1:1随机分组，接受以下治疗之一：（1）多西他赛（或紫杉醇）、卡铂、曲妥珠单抗（H）和帕妥珠单抗（P），共三个周期；或（2）T-DXd，共三个周期。进一步的治疗基于通过Prosigna检测确定的内在分子亚型：HER2富集型疾病患者（估计60%）继续相同治疗三个周期。雌激素受体（ER）阳性且为管腔型（估计30%）疾病的患者接受H和P治疗三个周期，并联合来曲唑和瑞博西尼治疗两个周期。ER阴性且为管腔型、基底样或正常样疾病的患者（估计10%），若影像学达到完全缓解，则继续相同治疗三个周期；若未达到完全缓解，则接受四个周期的剂量密集型表柔比星和环磷酰胺治疗。ARIADNE的主要终点是在分子HER2富集人群中局部评估的病理完全缓解率，定义为ypT0/Tis、ypN0，由对治疗分配不知情的病理学家确定（意向性分析（ITT））。关键次要终点包括事件发生时间终点（无事件生存、无复发生存、无远处复发生存和总生存）、安全性、健康相关生活质量和转化研究。
该研究已获得瑞典医疗产品管理局（Läkemedelsverket）、瑞典伦理审查局（Etikprövningsmyndigheten）和挪威药品和医疗器械临床试验伦理委员会以及所有参与中心的审查委员会的批准。在比利时、荷兰和意大利的伦理批准申请正在进行中。我们打算在科学期刊上发表该研究结果。研究结果将在临床试验（CT）结束后1年内提交至欧盟（EU）数据库。
欧盟CT注册号：2022 - 501504 - 95 - 00；ClinicalTrials.gov标识符：NCT05900206。
