EUDARIO/ENGOTov-48: A European multicenter randomised phase II trial on the combination of the HSP90 inhibitor ganetespib with carboplatin followed by maintenance treatment with niraparib (+/- ganetespib) compared to platinum-based combination-chemotherapy followed by niraparib in relapsed platinum-sensitive ovarian cancer patients.

person Nicole Concin Medical University of Innsbruck, Innsbruck, Austria info_outline Nicole Concin, Domenica Lorusso, Ioana Braicu, Isabelle Laure Ray-Coquard, Florence Joly, Philipp Harter, Pauline Wimberger, Jean-Pierre Lotz, Alain G Zeimet, Giovanni Scambia, Barbara Schmalfeldt, Claudio Zamagni, Francesco Raspagliesi, Alexander Mustea, Hanno Ulmer, Daniela Kramer, Matthias Dobbelstein, Eric Pujade-Lauraine, Jalid Sehouli, Ignace Vergote

Authors person Nicole Concin Medical University of Innsbruck, Innsbruck, Austria info_outline Nicole Concin, Domenica Lorusso, Ioana Braicu, Isabelle Laure Ray-Coquard, Florence Joly, Philipp Harter, Pauline Wimberger, Jean-Pierre Lotz, Alain G Zeimet, Giovanni Scambia, Barbara Schmalfeldt, Claudio Zamagni, Francesco Raspagliesi, Alexander Mustea, Hanno Ulmer, Daniela Kramer, Matthias Dobbelstein, Eric Pujade-Lauraine, Jalid Sehouli, Ignace Vergote Organizations Medical University of Innsbruck, Innsbruck, Austria, Fondazione Policlinico Universitario A. Gemelli IRCCS and MITO, Rome, Italy, Charité University Department of Gynecology, Campus Virchow Clinic, Berlin, Germany, Centre Léon-Bérard, Lyon, France, Centre François Baclesse, Caen, France, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany, Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany, Medical Oncology Department, Hospital Tenon (AP-HP), Paris, France, Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Policlinico S. Orsola-Malpighi Hospital, Bologna, Italy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, University Medicine Greifswald, Department of Gynaecology and Obstetrics, Greifswald, Germany, Innsbruck Medical University, Innsbruck, Austria, Interfaculty Institute for Biochemistry University of Tübingen, Tübingen, Germany, Institute of Molecular Oncology, Faculty of Medicine, University of Göttingen, Göttingen, Germany, GINECO, Paris, France, NOGGO, Berlin, Germany, BGOG & University Hospital Leuven, Leuven, Belgium Abstract Disclosures Research Funding Other Background: Carboplatin (C) mainly acts by forming interstrand crosslinks (ICL) within the DNA double helix, which can only be removed by the Fanconi Anemia (FA) pathway. HSP90 inhibitors destabilise a number of HSP90 client proteins, such as those governing the FA DNA repair pathway and the G2/M checkpoint (e.g. Chk1 and Wee1). Kramer et al. (Cell Death Differ, 2017) showed that the HSP90 inhibitor Ganetespib (G) virtually eliminates a functional FA DNA repair complex, therewith preventing the repair of DNA ICL in vitro and vivo. In parallel, G abrogated Chk1 and Wee1 expression and circumvented a G2/M arrest. Consequently, cells with unrepaired DNA damage rushed into mitosis, which resulted in massive tumour cell death. Furthermore, HSP90 inhibition has been shown to reduce the amount of BRCA1 in the cell therewith broadening sensitivity towards PARPi and preventing acquired PARP resistance. Our trial approach is tested in ovarian carcinomas with a mutant p53 background. EUDARIO (EUDRACT 017-004058-40) is funded by the European Commission (FP7 project GANNET53). Methods: Eligible patients have relapsed platinum-sensitive ovarian cancer, no limits in prior lines, high-grade (but clear cell) histology or carcinosarcoma, disease measurable or evaluable according to RECIST 1.1. Patients are randomised into 3 treatment arms (1:1:1), a) control arm: C+Gemcitabine or C+Paclitaxel (q3w, 6 cycles, investigator`s choice) followed by Niraparib, b+c) 2 experimental arms: C (AUC5, d1) + G (150mg/m 2 , d1) q3w 6 cycles followed by either Niraparib alone (arm b) or by Niraparib+G (arm c; G at 100mg/m 2 weekly, limited to 9 months). Niraparib (200/300mg/day) is given in case of SD, PR or CR after platinum-based treatment until disease progression. The main analysis will combine both experimental arms b+c and jointly compare them against arm a using log-rank test. Primary endpoint is PFS, secondary endpoints are PFS2, TFST, TSST, safety, ORR, PRO, OS. The first patient was dosed in January 2019. Clinical trial information: NCT03783949