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Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase III trial ARIEL3
  1. Andrew R Clamp1,
  2. Domenica Lorusso2,
  3. Amit M Oza3,
  4. Carol Aghajanian4,
  5. Ana Oaknin5,
  6. Andrew Dean6,
  7. Nicoletta Colombo7,
  8. Johanne I Weberpals8,
  9. Giovanni Scambia9,
  10. Alexandra Leary10,
  11. Robert W Holloway11,
  12. Margarita Amenedo Gancedo12,
  13. Peter C Fong13,
  14. Jeffrey C Goh14,15,
  15. David M O’Malley16,
  16. Deborah K Armstrong17,
  17. Susana Banerjee18,
  18. Jesus García-Donas19,
  19. Elizabeth M Swisher20,
  20. Terri Cameron21,
  21. Sandra Goble22,
  22. Robert L Coleman23 and
  23. Jonathan A Ledermann24
  1. 1Department of Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK
  2. 2Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies and Gynecologic Oncology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
  3. 3Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  4. 4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  5. 5Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  6. 6Department of Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia
  7. 7Gynecologic Cancer Program, University of Milan-Bicocca and European Institute of Oncology (IEO) IRCCS, Milan, Italy
  8. 8Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  9. 9Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Scientific Directorate, Rome, Italy
  10. 10Gynecological Unit, Gustave Roussy Cancer Center, INSERM U981, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Villejuif, France
  11. 11Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, Florida, USA
  12. 12Medical Oncology Department, Oncology Center of Galicia, La Coruña, Spain
  13. 13Medical Oncology Department, Auckland City Hospital and University of Auckland, Auckland, New Zealand
  14. 14Department of Oncology, Cancer Care Services, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
  15. 15University of Queensland, St Lucia, Queensland, Australia
  16. 16Division of Gynecologic Oncology, The Ohio State University, James Cancer Center, Columbus, Ohio, USA
  17. 17Oncology, Gynecology and Obstetrics, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA
  18. 18Gynecology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK
  19. 19Division of Medical Oncology, HM Hospitales—Centro Integral Oncológico Hospital de Madrid Clara Campal, Madrid, Spain
  20. 20Division of Gynecologic Oncology, University of Washington, Seattle, Washington, USA
  21. 21Clinical Science, Clovis Oncology UK Ltd, Cambridge, UK
  22. 22Biostatistics, Clovis Oncology, Inc, Boulder, Colorado, USA
  23. 23Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  24. 24Department of Oncology, UCL Cancer Institute, University College London and UCL Hospitals, London, UK
  1. Correspondence to Dr Domenica Lorusso, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; domenica.lorusso{at}policlinicogemelli.it
  • Present affiliation The present affiliation of Domenica Lorusso is: Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Scientific Directorate, Rome, Italy

  • Present affiliation The present affiliation of Robert L Coleman is: US Oncology Research, Texas, The Woodlands, USA

Abstract

Introduction In ARIEL3 (NCT01968213), the poly(adenosine diphosphate-ribose) polymerase inhibitor rucaparib significantly improved progression-free survival versus placebo regardless of biomarker status when used as maintenance treatment for recurrent ovarian cancer. The aim of the current analyses was to evaluate the efficacy and safety of rucaparib in subgroups based on progression-free interval following penultimate platinum, number of prior chemotherapies, and prior use of bevacizumab.

Methods Patients were randomized 2:1 to rucaparib 600 mg twice daily or placebo. Within subgroups, progression-free survival was assessed in prespecified, nested cohorts: BRCA-mutant, homologous recombination deficient (BRCA-mutant or wild-type BRCA/high genomic loss of heterozygosity), and the intent-to-treat population.

Results In the intent-to-treat population, median investigator-assessed progression-free survival was 8.2 months with rucaparib versus 4.1 months with placebo (n=151 vs n=76; HR 0.33, 95% CI 0.24 to 0.46, p<0.0001) for patients with progression-free interval 6 to ≤12 months, and 13.6 versus 5.6 months (n=224 vs n=113; HR 0.39, 95% CI 0.30 to 0.52, p<0.0001) for those with progression-free interval >12 months. Median progression-free survival was 10.4 versus 5.4 months (n=231 vs n=124; HR 0.42, 95% CI 0.32 to 0.54, p<0.0001) for patients who had received two prior chemotherapies, and 11.1 versus 5.3 months (n=144 vs n=65; HR 0.28, 95% CI 0.19 to 0.41, p<0.0001) for those who had received ≥3 prior chemotherapies. Median progression-free survival was 10.3 versus 5.4 months (n=83 vs n=43; HR 0.42, 95% CI 0.26 to 0.68, p=0.0004) for patients who had received prior bevacizumab, and 10.9 versus 5.4 months (n=292 vs n=146; HR 0.35, 95% CI 0.28 to 0.45, p<0.0001) for those who had not. Across subgroups, median progression-free survival was also significantly longer with rucaparib versus placebo in the BRCA-mutant and homologous recombination deficient cohorts. Safety was consistent across subgroups.

Conclusions Rucaparib maintenance treatment significantly improved progression-free survival versus placebo irrespective of progression-free interval following penultimate platinum, number of lines of prior chemotherapy, and previous use of bevacizumab.

  • ovarian cancer

Data availability statement

Requests for de-identified datasets for the results reported in this publication will be made available to qualified researchers following submission of a methodologically sound proposal to medinfo@clovisoncology.com. Data will be made available for such requests following online publication of this article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Data will be provided by Clovis Oncology. The redacted protocol for the ARIEL3 clinical study is available on ClinicalTrials.gov (NCT01968213). Clovis Oncology does not share identified participant data or a data dictionary.

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Data availability statement

Requests for de-identified datasets for the results reported in this publication will be made available to qualified researchers following submission of a methodologically sound proposal to medinfo@clovisoncology.com. Data will be made available for such requests following online publication of this article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Data will be provided by Clovis Oncology. The redacted protocol for the ARIEL3 clinical study is available on ClinicalTrials.gov (NCT01968213). Clovis Oncology does not share identified participant data or a data dictionary.

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Footnotes

  • ARC and DL contributed equally.

  • Contributors EMS, RLC, and JAL designed the study in collaboration with the funder. ARC, DL, AMO, CA, AO, AD, NC, JIW, GS, AL, RWH, MAG, PCF, JCG, DMO, DKA, SB, JG-D, EMS, RLC, and JAL treated patients. ARC, DL, AMO, CA, AO, AD, NC, JIW, GS, AL, RWH, MAG, PCF, JCG, DMO, DKA, SB, JG-D, EMS, RLC, and JAL acquired the data. All authors interpreted the data, contributed to the writing of the manuscript, reviewed and amended the drafts, and approved the final manuscript.

  • Funding The study was funded by Clovis Oncology, Inc. This work was supported in part by the Ann Rife Cox Chair in Gynecology and the Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund to RLC, and National Institute for Health Research Biomedical Research Centre at University College London to JAL (no grant numbers). CA is supported in part by the Memorial Sloan Kettering Cancer Center (support grant number P30 CA008748). This work was also supported by the United States Department of Defense Ovarian Cancer Research Program OC120506, a V Foundation Translational Award, and a Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number SU2C-AACR-DT16–15) to EMS. Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of Stand Up To Cancer. Medical writing support was provided by Andrew Croskery (Clovis Oncology, Ltd, London, UK), and editorial support funded by Clovis Oncology was provided by Frederique H Evans (Ashfield MedComms, an Ashfield Health company, Middletown, CT, USA).

  • Competing interests ARC has served on advisory boards for AstraZeneca, Eisai, and Tesaro/GlaxoSmithKline; has received research funding from Clovis Oncology and AstraZeneca; and has received travel and accommodation support for congress attendance from Clovis Oncology, AstraZeneca, and Roche. DL has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, and Tesaro/GlaxoSmithKline, Genmab; has received institutional research support from Merck, PharmaMar and Tesaro/GlaxoSmithKline; and received support for travel or accommodation from AstraZeneca, PharmaMar, Roche, and Tesaro/GlaxoSmithKline. AMO has served on steering committees for Clovis Oncology, AstraZeneca, and Tesaro (uncompensated). CA has served on a steering committee for AbbVie and Genentech; served on advisory boards for Clovis Oncology, AbbVie, Eisai/Merck, ImmunoGen, Mersana Therapeutics, Roche, and Tesaro; and received research grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech. AO has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, PharmaMar, Roche, and Tesaro; has received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and reports institutional research grant support from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Eisai, ImmunoGen, Merck/Merck Sharp & Dohme, Millennium Pharmaceuticals, PharmaMar, Roche, and Tesaro. AD has served in a consulting or advisory role for Precision Oncology Australia, Shire Pharmaceuticals, and Specialised Therapeutics Australia. NC has served in a consulting or advisory role for Clovis Oncology, Advaxis, AstraZeneca, BIOCAD, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, PharmaMar, Roche, Takeda, and Tesaro. JIW has received research support from AbbVie and AstraZeneca and served on advisory boards for AstraZeneca. GS has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, PharmaMar, Roche, and Tesaro. AL has served on advisory boards for Clovis Oncology, Ability Pharmaceuticals, AstraZeneca, BIOCAD, GamaMabs, Genmab/Seattle Genetics, Gritstone, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, and Tesaro; steering committee for Merck Sharp & Dohme; reports institutional support for clinical trials or academic research from Clovis Oncology, Ability Pharmaceuticals, Agenus, AstraZeneca, Incyte, Inivata, Iovance, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tesaro; and reports boarding and travel expenses for congress activities from Clovis Oncology, AstraZeneca, and Roche. RWH has served on speakers bureaus for Clovis Oncology, AstraZeneca, and Tesaro, and on advisory boards for Clovis Oncology and AstraZeneca. MAG has served on speakers’ bureaus for Clovis Oncology, AstraZeneca, PharmaMar, and Roche. PCF has served on advisory boards for Clovis Oncology and AstraZeneca and received honoraria from AstraZeneca. JCG has received honoraria from AstraZeneca and Bristol-Myers Squibb; served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Tesaro; served on speakers’ bureaus for AstraZeneca, Ipsen, and Merck Sharp & Dohme; and received support for travel and/or accommodation from Astellas and AstraZeneca. DMO has served on advisory boards for Clovis Oncology, AbbVie, AstraZeneca, Eisai, Genentech/Roche, Genelux, Iovance Biotherapeutics, Janssen, Novocure, Regeneron, and Tesaro; has served on steering committees for Clovis Oncology, Agenus, Amgen, and Novocure; has served as a consultant for AbbVie, Ambry, AstraZeneca, Genentech/Roche, Gynecologic Oncology Group Foundation, and Tesaro; has given a presentation on ovarian cancer at the National Comprehensive Cancer Network; and his institution has received research support from Clovis Oncology, AbbVie, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, ERGOMED Clinical Research, Genentech, Gynecologic Oncology Group, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen Research and Development, Ludwig Institute for Cancer Research, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, TRACON Pharmaceuticals, VentiRx, and Yale University. DKA has served as a scientific advisor for Morphotek and received research funding from Clovis Oncology, Advaxis, AstraZeneca, Pfizer, Syndax, and Tesaro. SB has served on advisory boards and received honoraria from Clovis Oncology, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Merck Sereno, Merck Sharp & Dohme, Mersana, Pfizer, Roche, Seattle Genetics, and Tesaro; received honoraria for lectures from AstraZeneca/Merck Sharp & Dohme, GlaxoSmithKline, Pfizer, Roche, and Tesaro; received support for travel or accommodation from NuCana and Tesaro; and reports institutional funding from AstraZeneca, GlaxoSmithKline, and Tesaro. JG-D has received research funding from AstraZeneca, Pierre Fabre, and Pfizer; received personal fees from Clovis Oncology, Astellas, Pierre Fabre, and Pfizer; and received nonfinancial support from Astellas, Pierre Fabre, and Pfizer. TC and SG are employees of Clovis Oncology and may own stock or have stock options in that company. RLC reports grants from Clovis Oncology, AstraZeneca, Gateway Foundation, Janssen, Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund, Merck, National Institutes of Health, Roche/Genentech, and V-Foundation; has served as an advisor to Clovis Oncology, Agenus, AstraZeneca, GamaMabs, Genmab, Janssen, OncoQuest, Pfizer (Medivation), Regeneron, Roche/Genentech, and Tesaro; and has an endowment as the Ann Rife Cox Chair in Gynecology. JAL has received lecture fees from Clovis Oncology, AstraZeneca, and Pfizer; served on advisory boards for Clovis Oncology, Artios Pharma, AstraZeneca, Cristal Therapeutics, Merck/Merck Sharp & Dohme, Pfizer, Regeneron, Roche, Seattle Genetics, and Tesaro; and received research grants from AstraZeneca and Merck/Merck Sharp & Dohme.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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