LBA34 - ENGOT-ov48/EUDARIO: European trial on enhanced DNA repair inhibition in ovarian cancer

Background

HSP90 inhibitors (HSP90i) destabilize several HSP90 client proteins, such as those governing the Fanconi Anemia DNA repair pathway, the G2/M checkpoint (eg Chk1 and Wee1), and BRCA1. This supports using HSP90i in combination with Carboplatin (C) to induce mitotic catastrophe and with PARPi to create a BRCA-like phenotype in ovarian cancer (OC).

Methods

This is a multicentre, open-label, three-arm randomized Phase II trial assessing the HSP90i Ganetespib (G) in combination with C followed by maintenance treatment with Niraparib (N) (experimental arm B) versus G/C followed by G&N (experimental arm C) versus standard platinum-based chemotherapy combinations followed by N (standard arm A) in patients with platinum-sensitive (pls) OC. Key inclusion criteria were high-grade epithelial OC (including carcinosarcoma), pls relapse >6mo after previous platinum treatment, and no restrictions in nr of prior lines. A large biobank was established from patients enrolled in this trial. The primary endpoint was PFS.

Results

122 OC patients were enrolled. Median PFS in the combined arms B+C was 8.3 mo (95%CI: 6.9-9.7) compared to 8.9 mo (95%CI: 7.4-11.6) in the standard arm A (HR:1.2, 95%CI: 0.8-1.7; p=0.53). Secondary endpoints (PFS2, TFST, TSST, OS, ORR, PRO) were similar. During chemotherapy, the number and severity of AEs was higher in the standard arm compared to the experimental arms. During maintenance therapy, arm C (G&N) had a higher rate and severity of AEs compared to the arms A/B (N only). Most common AEs related to G were of haematotoxic, diarrhoea, nausea, vomiting and asthenia. Translational analyses eg included the evaluation of 27 CTC (circulating tumour cell)-associated gene transcripts in paired blood samples taken at baseline (n=96) and at progression (n=52). CDH5 and FXYD3 transcripts at baseline were prognostic factors for OS, while a selection towards ERBB2 transcripts during treatment measured at the time of relapse was associated with poor OS.

Conclusions

EUDARIO is the first trial to combine an HSP90i with C and PARPi in OC and has not shown improved outcome. Based on its unique biobank, it provides valuable translational findings, such as encouraging the analysis of liquid biopsies for therapy monitoring and prognostication in patients with pls OC.

Clinical trial identification

ENGOT-ov48; EudraCT: 2017-004058-40 NCT03783949.

Editorial acknowledgement

Legal entity responsible for the study

Katholik University of Leuven, Belgium and BGOG.

Funding

The ENGOT-ov48/EUDARIO trial was fully funded by the seventh framework programme (FP7) project of the European Union (Grant agreement no 602602). Specific translational research received additional funded by Margaretha Hehberger-Cancer Research Fund, the National Cancer Institute 2R01CA176647, the Carol Baldwin Foundation and an independent research grant by ANGLE.

Disclosure

N. Concin: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, Seattle Genetics, Mersana, eTheRNAimmunotherapies, Seagen, AkesoBio, EiSai, ImmunoGen, Kartos; Financial Interests, Personal, Invited Speaker: NOGGO, Eickeler, Mediseminar, Medconcept, NSGO-CTU; Non-Financial Interests, Principal Investigator, PI in a clinical trial: Aldeyra, Clovis, Kartos, Mersana, Seagon; Non-Financial Interests, Other, president: ESGO; Non-Financial Interests, Other, Co-Chair Early Drug Development Network of ENGOT: ENGOT; Other, travel expenses: Roche, Genmab, Amgen; Other, compensation received for educational: MSD, Medscape Oncology; Other, Compensation received for educational: TouchIME; Other, compensation received for educational activity: Kartos. T. Van Gorp: Financial Interests, Institutional, Advisory Board: AbbVie, BioNTech, ImmunoGen, Incyte, Karyopharm, Seagen, Zentalis; Financial Interests, Institutional, Advisory Board, Jan-2021 until 09-2022: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Eisai, ImmunoGen, MSD/Merck; Financial Interests, Institutional, Other, Travel costs: AstraZeneca, GSK, MSD/Merck, PharmaMar; Financial Interests, Institutional, Writing Engagement: Cancer Communications and Consultancy Ltd; Financial Interests, Institutional, Advisory Board, Jan-2021: Eisai; Financial Interests, Institutional, Advisory Board, May-2021 until present: GSK; Financial Interests, Institutional, Invited Speaker, Apr 2022: GSK; Financial Interests, Institutional, Advisory Board, Apr-2021 until present: MSD/Merck; Financial Interests, Institutional, Advisory Board, Feb-2021: OncXerna Therapeutics; Financial Interests, Institutional, Advisory Board, Feb 2023 until present: Tubulis; Financial Interests, Institutional, Research Grant, Oct-2020 until Oct-2021: Amgen; Financial Interests, Institutional, Research Grant, Oct-2020 until Oct-2022: Roche; Financial Interests, Institutional, Research Grant, Jan 2022 until Mar 2023: AstraZeneca; Non-Financial Interests, Leadership Role, Chair of BGOG (unremunerated): Belgian and Luxembourg Gynaecological Oncology Group (BGOG); Non-Financial Interests, Member of Board of Directors, Member of the strategic group (unremunerated): European Network for Gynaecological Oncological Trial groups (ENGOT). D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: Clovis Oncology, GSK; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Corcept, Oncoinvest, Sutro; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Genmab, Immunogen, Seagen; Financial Interests, Personal, Advisory Board, Invited Speaker of advisory board: Novocure; Financial Interests, Personal, Other, Consultancy: AstraZeneca, Clovis Oncology, GSK, Genmab, Immunogen, MSD, Novartis, PharmaMar, Seagen; Financial Interests, Personal, Other, Colsuntancy: Novartis; Financial Interests, Institutional, Funding, Clnical trial/contracted research: Alkermes, AstraZeneca, Clovis Oncology, GSK, MSD, Seagen, Corcept; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Funding, Grant for founding academic trials: Clovis Oncology, GSK, MSD, Pharma&, PharmaMar; Financial Interests, Institutional, Coordinating PI, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab, Cercept; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation received: Clovis Oncology, Immunogen, Incyte, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Non-Financial Interests, Member, Board of Directors: GCIG; Non-Financial Interests, Member, President Elected: MITO; Non-Financial Interests, Member, Coordinating: ENGOT; Other, Grants for traveling: AstraZeneca, Menarini, Clovis Oncology, GSK. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, adaptimmun, Esai, Eisai, Sutro, Adaptimmune, Daiichi Sankyo, Immunogen, Seagen, PMVpharma; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Principal Investigator: PAOLA1; Non-Financial Interests, Other, President: GINECO. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche, Eisai, Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Exact Sciences, MSD, GSK, Gilead, Seagen; Financial Interests, Institutional, Local PI: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Medivation, AbbVie, Array BioPharma, Morphotek, Synthon, Daichii Sankyo, MSD, GSK, Gilead; Financial Interests, Personal, Other, Member of an Independent Data Monitoring Committee for an international clinical trial: AstraZeneca; Non-Financial Interests, Other, member of the Scientific Committee: LOTO Onlus, Susan J Komen Emilia-Romagna, Mamazone Sudtirol; Other, travel accomodation and partecipation expenses for scientific congresses: Roche, Novartis, Pfizer, Daichii Sankyo, MSD, GSK, Gilead, AstraZeneca. P. Harter: Financial Interests, Personal, Advisory Board, Value includes honoraria for lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, includes honoraria for lectures: GSK, Roche, MSD; Financial Interests, Personal, Invited Speaker: Amgen, Stryker, Zailab, Eisai, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Clovis, Immunogen, Novartis, Mersana, Miltenyi, Exscientia, Corcept, BionTech, Karyopharm, AbbVie; Financial Interests, Personal, Other, IDMC member: Sotio; Financial Interests, Institutional, Trial Chair: AstraZeneca, Roche, GSK, Immunogen; Financial Interests, Institutional, Local PI: Genmab; Financial Interests, Institutional, Funding: Seagen, Clovis; Financial Interests, Institutional, Other, Co-investigator: Novartis; Non-Financial Interests, Principal Investigator: AstraZeneca; Other, Travel support for conference: AstraZeneca. J. Sehouli: Financial Interests, Personal and Institutional, Advisory Board: tesaro, GSK, AZ; Financial Interests, Personal, Advisory Board: Pharma Mar, Bayer, Vifor Pharma, Hexal AG, Novartis, Eisai, Esteve, Incyte Biosciences, Phytolife Nutrition, JenaPharm, Kyowa Kirin, Oncoinvent AS, Daiichi, Metronic Covidien, Amgen, Merck/Pfizer, Novocure, Oncoinvent, Intuitive, Seagan, Mundipharma, Sanofi-Aventis, Immunogen, Tubulis, Bristol Myers, Kayopharm; Financial Interests, Personal and Institutional, Research Funding: Clovis, Roche, MSD, Bayer Vitoal; Financial Interests, Institutional, Research Funding: Lilly, Mural, Iqvia. A.G. Zeimet: Financial Interests, Personal, Funding: EU, FWF, AstraZeneca, Roche, Pharma Mar; Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Roche Diagnostics, Novartis, Amgen, MSD, AstraZeneca, Celegene, Pfizer, Pharma Mar, GSK, Tesaro, Clovis, Biocad, Eisai Inc., AbbVie, Sandoz; Financial Interests, Personal, Sponsor/Funding: Roche, Novartis, Amgen, MSD, AstraZeneca, Eisai Inc., Pharma Mar, GSK, Tesaro, Roche Diagnostics, Celgene, Daiichi Sankyo, Gilead. V. Salutari: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai; Financial Interests, Personal, Invited Speaker: MSD, GSK; Financial Interests, Institutional, Local PI: MSD, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: MSD. O. Tredan: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Pierre Fabre Oncologie, Seagen, Daiichi Sankyo, Gilead, Eisai, Stemline-Menarini, Veracyte, Exact Sciences. M. Dobbelstein: Financial Interests, Personal, Advisory Board: Scinai Immunotherapeutics. I. Braicu: Financial Interests, Institutional, Research Grant: MSD, AstraZeneca, MSD, Eisai, GSK, Bayer, Roche, Roche Diagnostics; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Immunogen, TORLBio, MSD; Non-Financial Interests, Personal, Leadership Role: North Eastern Society of Gynecological Oncology. I.B. Vergote: Financial Interests, Personal, Advisory Board: Akesobio, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann - La Roche, Genmab, GSK, ITM, Jazzpharma, Karyopharm, MSD, Novocure, Oncoinvent, Sanofi, Regeneron, Seagen, Sotio, Zentalis; Financial Interests, Personal, Speaker, Consultant, Advisor: Agenus, AstraZeneca, Corcept, Daiichi, Exelixis, Genmab, F. Hoffmann-La Roche, Immunogen, Kronos Bio, Mersana, OncXerna, Verastem Oncology. All other authors have declared no conflicts of interest.