Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer

Published:March 26, 2018DOI:


      • Ovarian cancer, the deadliest of gynecological cancers, has a 70% recurrence rate.
      • Ovarian cancer presents homologous recombination deficiencies in 50% of cases.
      • PARP inhibitors manifest synthetic lethality in BRCA mutated cancers.
      • Rucaparib, a PARP inhibitor, is effective in patients with “BRCAness” phenotype.
      • A complex HRD assay predicts response to Rucaparib by defining the degree of LOH.


      Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation. On March 2017, Niraparib, was approved as maintenance treatment of patients with recurrent epithelial ovarian, who are in complete or partial response to platinum-based chemotherapy, independently of BRCA mutation. Rucaparib inhibits PARP-1, 2 and 3, PARP-4, -12, -15 and -16, as well as tankyrase 1 and 2. On December 2016, it was granted accelerated approval by the FDA, based on data from two multicenter, single arm, phase II trials that evaluated the efficacy of Rucaparib in patients with deleterious, germline and/or somatic BRCA mutation-associated, advanced OC, who have been treated with two or more lines of chemotherapy. The maximum tolerated dose reported was 600 mg twice a day administered orally. Phase III studies are currently ongoing to further validate the efficacy of Rucaparib in the treatment setting and explore its usefulness in a maintenance setting as well. The focus of our review is to report the most recent investigations and clinical progress regarding Rucaparib for treatment of recurrent ovarian cancer.


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      1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online Exit Disclaimer [accessed October 13, 2017].

        • Jayson G.C.
        • Kohn E.C.
        • Kitchener H.C.
        • Ledermann J.A.
        Ovarian cancer.
        Lancet. 2014; 384: 1376-1388
        • Roco A.
        • Cayún J.
        • Contreras S.
        • Stojanova J.
        • Quiñones L.
        Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?.
        Front Genet. 2014; 14: 391
        • Camps C.
        • Sirera R.
        • Iranzo V.
        • Taron M.
        • Rosell R.
        Gene expression and polymorphisms of DNA repair enzymes: cancer susceptibility and response to chemotherapy.
        Clin Lung Cancer. 2007; 8: 369-375
        • Lord C.J.
        • Ashworth A.
        The DNA damage response and cancer therapy.
        Nature. 2012; 481: 287-294
        • Roy R.
        • Chun J.
        • Powell S.N.
        BRCA1 and BRCA2: different roles in a common pathway of genome protection.
        Nat Rev Cancer. 2012; 12: 68-78
        • Caestecker K.W.
        • Van de Walle G.R.
        The role of BRCA1 in DNA double-strand repair: past and present.
        Exp Cell Res. 2013; 319: 575-587
        • Somasundaram K.
        BRCA1 and BRCA1 genes and inherited breast and/or ovarian cancer: benefits of genetic testing.
        Indian J Surg Oncol. 2010; 1: 245-249
        • Cipak L.
        • Watanabe N.
        • Bessho T.
        The role of BRCA2 in replication-coupled DNA interstrand cross-link repair in vitro.
        Nat Struct Mol Biol. 2006; 13: 729-733
        • De Picciotto N.
        • Cacheux W.
        • Roth A.
        • Chappuis P.O.
        • Labidi-Galy S.I.
        Ovarian cancer: status of homologous recombination pathway as a predictor of drug response.
        Crit Rev Oncol Hematol. 2016; 101: 50-59
        • Gudmundsdottir K.
        • Ashworth A.
        The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability.
        Oncogene. 2006; 25: 5864-5874
        • Cancer Genome Atlas Network
        Integrated genomic analyses of ovarian carcinoma.
        Nature. 2011; 474: 609-615
        • Pennington K.P.
        • Walsh T.
        • Harrell M.I.
        • Lee M.K.
        • Pennil C.C.
        • Rendi M.H.
        • et al.
        Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
        Clin Cancer Res. 2014; 20: 764-775
        • Marchetti C.
        • McNeish I.A.
        How to measure homologous recombination deficiency in ovarian cancer.
        Cancer Breaking News. 2017; 5: 15-20
        • Swisher E.M.
        • Lin K.K.
        • Oza A.M.
        • Scott C.L.
        • Giordano H.
        • Sun J.
        • et al.
        Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2017; 18: 75-87
        • Friend S.H.
        • Oliff A.
        Emerging uses for genomic information in drug discovery.
        N Engl J Med. 1998; 338: 125-126
        • Ledermann J.A.
        • Drew Y.
        • Kristeleit R.S.
        Homologous recombination deficiency and ovarian cancer.
        Eur J Cancer. 2016; 60: 49-58
        • Benafif S.
        • Hall M.
        An update on PARP inhibitors for the treatment of cancer.
        Onco Targets Ther. 2015; 8: 519-528
        • McCabe N.
        • Turner N.C.
        • Lord C.J.
        • Kluzek K.
        • Bialkowska A.
        • Swift S.
        • et al.
        Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
        Cancer Res. 2006; 66: 8109-8115
        • Liu X.
        • Shi Y.
        • Maag D.X.
        • Palma J.P.
        • Patterson M.J.
        • Ellis P.A.
        • et al.
        Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor.
        Clin Cancer Res. 2012; 18: 510-523
        • Murai J.
        • Huang S.Y.
        • Das B.B.
        • Renaud A.
        • Zhang Y.
        • Doroshow J.H.
        • et al.
        Cancer Res. 2012; 72: 5588-5599
        • Shen Y.
        • Aoyagi-Scharber M.
        • Wang B.
        Trapping poly(ADP-ribose) polymerase.
        J Pharmacol Exp Ther. 2015; 353: 446-457
        • Patel A.G.
        • Sarkaria J.N.
        • Kaufmann S.H.
        Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.
        Proc Natl Acad Sci USA. 2011; 108: 3406-3411
        • Scott C.L.
        • Swisher E.M.
        • Kaufmann S.H.
        Poly(ADP-ribose) polymerase inhibitors: recent advances and future development.
        J Clin Oncol. 2015; 33 (1397-06)
        • Liu J.F.
        • Matulonis U.A.
        What is the place of PARP inhibitors in ovarian cancer treatment?.
        Curr Oncol Rep. 2016; 18: 29
        • Pujade-Lauraine E.
        • Ledermann J.A.
        • Selle F.
        • Gebski V.
        • Penson R.T.
        • Oza A.M.
        • et al.
        Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1274-1284
        • Kaufman B.
        • Shapira-Frommer R.
        • Schmutzler R.K.
        • Audeh M.W.
        • Friedlander M.
        • Balmaña J.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J Clin Oncol. 2015; 33: 244-250
        • Kanjanapan Y.
        • Lheureux S.
        • Oza A.M.
        Niraparib for the treatment of ovarian cancer.
        Expert Opin Pharmacother. 2017; 18: 631-640
        • Mirza M.R.
        • Monk B.J.
        • Herrstedt J.
        • Oza A.M.
        • Mahner S.
        • Redondo A.
        • et al.
        Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
        N Engl J Med. 2016; 375: 2154-2164
        • Coleman R.L.
        • Oza A.M.
        • Lorusso D.
        • Aghajanian C.
        • Oaknin A.
        • Dean A.
        • et al.
        Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 390: 1949-1961
        • Jenner Z.B.
        • Sood A.K.
        • Coleman R.L.
        Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy.
        Fut Oncol. 2016; 12: 1439-1456
      2. Rubraca (rucaparib) [prescribing information]. Clovis Oncology, Boulder, CO; 2017.

        • Dockery L.E.
        • Gunderson C.C.
        • Moore K.N.
        Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer.
        Onco Targets Ther. 2017; 10: 3029-3037
      3. DrugBank [Internet]. Edmonton (AB): Metabolomics Innovation Centre (TMIC), University of Alberta. c2006 – [cited 2017 November 8]. Available from: <>.

        • Plummer R.
        • Jones C.
        • Middleton M.
        • Wilson R.
        • Evans J.
        • Olsen A.
        • et al.
        Phase I study of the Poly (ADP-Ribose) polymerase Inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
        Clin Cancer Res. 2005; 14: 7917-7923
        • Wang D.D.
        • Li C.
        • Sun W.
        • Zhang S.
        • Shalinsky D.R.
        • Kern K.A.
        • et al.
        PARP activity in peripheral blood lymphocytes as a predictive biomarker for PARP inhibition in tumor tissues – a population pharmacokinetic/pharmacodynamic analysis of Rucaparib.
        Clin Pharmacol Drug Dev. 2015; 4: 89-98
        • Drew Y.
        • Ledermann J.
        • Hall G.
        • Rea D.
        • Glasspool R.
        • Highley M.
        • et al.
        Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.
        Br J Cancer. 2016; 114: 21
        • Wahlberg E.
        • Karlberg T.
        • Kouznetsova E.
        • Markova N.
        • Macchiarulo A.
        • Thorsell A.G.
        • et al.
        Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors.
        Nat Biotechnol. 2012; 30: 283-288
        • Kristeleit R.
        • Shapiro G.I.
        • Burris H.A.
        • Oza A.M.
        • LoRusso P.
        • Patel M.R.
        • et al.
        A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors.
        Clin Cancer Res. 2017; 23 (4095-06)
        • O'Sullivan Coyne G.
        • Chen A.P.
        • Meehan R.
        • Doroshow J.H.
        PARP inhibitors in reproductive system cancers: current use and developments.
        Drugs. 2017; 77: 113-130
      4. U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Approved drugs, Rucaparib [internet]. Silver Spring, MD: U.S. Food and Drug Administration 2009, July 24. Available from: <> [accessed 28 November 2017].

      5. [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb 29. Identifier: NCT02855944, ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients; 2016, Aug 4 [citation 2017, Jul 26 ]. Available from:

      6. Oza AM, Lorusso D, Oaknin A, Safra T, Swisher EM, Bondarenko IM, et al. ARIEL4: An international, multicenter, randomized phase 3 study of the PARP Inhibitor Rucaparib vs chemotherapy in germline or somatic BRCA1-or BRCA2-mutated, relapsed, high-grade ovarian carcinoma [abstract TPS5603]. ASCO Annual Meeting, Chicago (IL), June 2017.

        • McCormick A.
        • Swaisland H.
        In vitro assessment of the roles of drug transporters in the disposition and drug–drug interaction potential of olaparib.
        Xenobiotica. 2017; 47: 903-915
        • Kikuchi R.
        • Lao Y.
        • Bow D.A.
        • et al.
        Prediction of clinical drug–drug interactions of veliparib (ABT-888) with human renal transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K).
        J Pharm Sci. 2013; 102: 4426-4432
        • Mariappan L.
        • Jiang X.Y.
        • Jackson J.
        • Drew Y.
        Emerging treatment options for ovarian cancer: focus on rucaparib.
        Int J Womens Health. 2017; 9: 913-924
        • Fojo T.
        • Bates S.
        Mechanisms of resistance to PARP inhibitors-three and counting.
        Cancer Discov. 2013; 3: 20-23
        • Ang J.E.
        • Gourley C.
        • Powell C.B.
        • High H.
        • Shapira-Frommer R.
        • Castonguay V.
        • et al.
        Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study.
        Clin Cancer Res. 2013; 19: 5485-5493
        • Kaye S.B.
        Progress in the treatment of ovarian cancer-lessons from homologous recombination deficiency-the first 10 years.
        Ann Oncol. 2016; 27: i1-i3
        • Oza A.
        • Cibula D.
        • Oaknin A.
        • Poole C.
        • Mathijssen R.H.
        • Sonke G.S.
        • et al.
        Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.
        Lancet Oncol. 2015; 16: 87-97
        • Ibrahim Y.H.
        • Garcia-Garcia C.
        • Serra V.
        • Torres-Lockhart K.
        • Prat A.
        • Anton P.
        • et al.
        PI3K inhibition impairs BRCA1/2 expression and sensitises BRCA-proficient triple-negative breast cancer to PARP inhibition.
        Cancer Discov. 2012; 2: 1036-1047
        • Wilson R.H.
        • Evans T.J.
        • Middleton M.R.
        • Molife L.R.
        • Spicer J.
        • Dieras V.
        • et al.
        A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours.
        Br J Cancer. 2017; 116: 884-892
        • Liu J.F.
        • Barry W.T.
        • Birrer M.
        • Lee J.M.
        • Buckanovich R.J.
        • Fleming G.F.
        • et al.
        Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
        Lancet Oncol. 2014; 15: 1207-1214