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  • Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety

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Original article
Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety
  1. Rebecca S Kristeleit1,
  2. Ana Oaknin2,
  3. Isabelle Ray-Coquard3,
  4. Alexandra Leary4,
  5. Judith Balmaña2,
  6. Yvette Drew5,
  7. Amit M Oza6,
  8. Ronnie Shapira-Frommer7,
  9. Susan M Domchek8,
  10. Terri Cameron9,
  11. Lara Maloney10,
  12. Sandra Goble10,
  13. Domenica Lorusso11,
  14. Jonathan A Ledermann1 and
  15. Iain A McNeish12
  1. 1 UCL Cancer Institute, University College London and UCL Hospitals, London, UK
  2. 2 Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
  3. 3 Centre Léon Bérard and University Claude Bernard and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Lyon, France
  4. 4 Gustave Roussy Cancer Center, INSERM U981, and GINECO, Villejuif, France
  5. 5 Northern Centre for Cancer Care, Newcastle Hospitals NHS Foundation Trust and Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
  6. 6 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  7. 7 Chaim Sheba Medical Center, Tel HaShomer, Israel
  8. 8 Abramson Cancer Center, Basser Center for BRCA, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  9. 9 Clovis Oncology UK Ltd, Cambridge, UK
  10. 10 Clovis Oncology, Inc, Boulder, Colorado, USA
  11. 11 Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
  12. 12 Imperial College London, London, UK
  1. Correspondence to Dr Rebecca S Kristeleit, University College London Cancer Institute, 72 Huntley St., London, WC1E 6DD, UK; r.kristeleit{at}ucl.ac.uk

Abstract

Objective To report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.

Methods Efficacy was analyzed in platinum-sensitive patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who had high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious BRCA1 or BRCA2 mutation and received two or more prior chemotherapies (including two or more platinum-based therapies). The primary end point was investigator-assessed, confirmed objective response rate (visit cut-off: April 10, 2017). Safety was analyzed in patients with ovarian cancer, regardless of BRCA mutation status or lines of prior chemotherapies, who received at least one dose of rucaparib 600 mg in either study (visit cut-off: December 31, 2017).

Results In the integrated platinum-sensitive efficacy population (n=79), objective response rate was 64.6% (95% CI, 53.0 to 75.0); 10.1% (8/79) of patients had a complete response and 54.4% (43/79) had a partial response. Median duration of response was 294 days (95% CI, 224 to 393). In the integrated safety population (n=565), the most common any-grade treatment-emergent adverse events were nausea (77.7%, 439/565), asthenia/fatigue (74.7%, 422/565), vomiting (45.8%, 259/565), and hemoglobin decreased (44.2%, 250/565). Treatment-emergent adverse events led to treatment interruption, dose reduction, or discontinuation in 60.2% (340/565), 46.0% (260/565), and 16.8% (95/565) of patients.

Conclusions In patients with platinum-sensitive, BRCA-mutated ovarian cancer, rucaparib demonstrated antitumor activity and is the first and currently the only poly(ADP-ribose) polymerase inhibitor approved by the European Commission as treatment for this population. The safety analysis used a more recent visit cut-off date and larger population than previously published, was consistent with prior reports, and was the basis for the treatment-indication safety population in rucaparib’s recently updated European Union label.

  • ovarian cancer

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/ijgc-2019-000623

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    Footnotes

    • Contributors RSK, RS-F, IAM, and LM conceived and designed the studies. RSK, AO, IR-C, AL, JB, YD, AMO, RS-F, SMD, TC, LM, SG, DL, JAL, and IAM were involved in acquisition, analysis, or interpretation of data for the work. RSK, AO, IR-C, AL, JB, YD, AMO, RS-F, SMD, TC, LM, SG, DL, JAL, and IAM were involved in drafting the manuscript and provided critical feedback. RSK, AO, IR-C, AL, JB, YD, AMO, RS-F, SMD, TC, LM, SG, DL, JAL, and IAM approved the final manuscript.

    • Funding This work was funded by Clovis Oncology, Inc. Authors who are employees of Clovis Oncology were involved in the design of the studies reported in this publication, as well as the analysis and interpretation of the data, writing of the report, and approval of the paper for publication. The sponsor was responsible for the collection, analysis, and interpretation of the data. One or more of the trials discussed in this publication were supported by the NIHR/Wellcome UCH Clinical Research Facility and Experimental Cancer Medicine Centres at UCL, Newcastle, and Imperial. RSK is supported in part by the UCH/UCL Biomedical Research Centre. JAL is an NIHR Senior Investigator. Writing and editorial assistance funded by Clovis Oncology was provided by Nathan Yardley, PhD, Mollie Marko, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT).

    • Competing interests RSK has served on advisory boards for Clovis Oncology, Roche, and Tesaro. 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. IR-C has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, PharmaMar, Roche, and Tesaro and received support for travel or accommodation from AstraZeneca and Roche. AL has served on advisory boards for Clovis Oncology, AstraZeneca, Gritstone, Genmab/Seattle Genetics, and Tesaro; reports institutional support for clinical trials from Clovis Oncology and AstraZeneca; and reports boarding and travel expenses for congress activities from Clovis Oncology, AstraZeneca, and Roche. JB has served on advisory boards for Clovis Oncology, AstraZeneca, and Bristol-Myers Squibb and received support for travel from AstraZeneca. YD has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab, and Tesaro; serves on a trial steering committee for AstraZeneca; has received research funding from Clovis Oncology; her institution, Newcastle Hospitals NHS Foundation Trust, has received reimbursement of study costs from Clovis Oncology for a clinical trial described in this manuscript. YD and her employer (Newcastle University) receive royalties in recognition of their role in the preclinical development of rucaparib. AMO has served on steering committees for Clovis Oncology, AstraZeneca, and Tesaro. RS-F has served on advisory boards for Clovis Oncology. SMD has received honoraria from Clovis Oncology, AstraZeneca, and Bristol-Myers Squibb, and her institution has received research funding from Clovis Oncology and AstraZeneca. TC, LM, and SG are employees of Clovis Oncology and may own stock or have stock options in that company. DL has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, Genmab, Merck, and Tesaro and received institutional research support from Clovis Oncology, Merck, PharmaMar, and Tesaro. JAL has served in an advisory role for Clovis Oncology, Artios Pharma, AstraZeneca, Merck/Merck Sharp & Dohme, Pfizer, Seattle Genetics, and Tesaro; is chair of an independent Data Monitoring Committee for Regeneron; and has served on speakers' bureaus for and received research grants from AstraZeneca and Merck/Merck Sharp & Dohme. IAM has served on advisory boards for Clovis Oncology, AstraZeneca, Takeda, and Tesaro and receives institutional funding from AstraZeneca.

    • Patient consent for publication Not required.

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

    • Data availability statement For more information about this manuscript, please contact the corresponding author. Data that are summarized in this manuscript are from the clinical studies ARIEL2 (NCT01891344) and Study 10 (NCT01482715), both of which were sponsored by Clovis Oncology, Inc. (Boulder, CO). Efficacy data in this manuscript are summarized for patients who enrolled on ARIEL2 or Study 10 by October 1, 2015. Safety follow-up data are included for the period ending on December 31, 2017. For more detailed information about these studies or the data summarized herein, please contact: medinfo@clovisoncology.com.