PARP inhibitors in ovarian cancer: Current status and future promise


      • Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting new classes of targeted agents for ovarian cancer treatment.
      • PARP inhibitors have demonstrated single-agent activity in BRCA-related ovarian cancer and sporadic high grade serous ovarian cancer.
      • Phase III PARP inhibitor studies have been launched for newly diagnosed germline BRCA cancers and platinum sensitive recurrent ovarian cancer.


      Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Do K.
        • Chen A.P.
        Molecular pathways: targeting PARP in cancer treatment.
        Clin Cancer Res. 2012; 19: 977-984
        • Lord C.J.
        • Ashworth A.
        The DNA damage response and cancer therapy.
        Nature. 2012; 481: 287-294
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • Parker K.M.
        • Flower D.
        • Lopez E.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-Ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • Tutt A.N.
        • Johnson D.A.
        • Richardson T.B.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Fong P.C.
        • Boss D.S.
        • Yap T.A.
        • Tutt A.
        • Wu P.
        • Mergui-Roelvink M.
        • et al.
        Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA-carriers.
        N Engl J Med. 2009; 361: 123-134
        • Ledermann J.A.
        • Harter P.
        • Gourley C.
        • Friedlander M.
        • Vergote I.
        • Rustin G.
        • et al.
        Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
        N Engl J Med. 2012; 366: 1382-1392
        • Integrated genomic analyses of ovarian cancer
        Nature. 2011; 474: 609-615
        • Ledermann J.A.
        • Harter P.
        • Gourley C.
        • Friedlander M.
        • Vergote I.
        • Gordon J.S.
        • et al.
        Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation.
        Clin Oncol. 2013; 31 ([Suppl.; abstr 5505])
        • Rouleau M.
        • Patel A.
        • Hendzel M.J.
        • Kaufmann S.H.
        • Poirier G.G.
        PARP inhibition: PARP1 and beyond.
        Nat Rev Cancer. 2010; 10: 293-301
        • Ag Patel
        • Jn Sarkaria
        • Kaufmann S.H.
        Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.
        Proc Natl Acad Sci U S A. 2011; 108: 3406-3411
        • Murai J.
        • Huang S.Y.
        • Das B.B.
        • Renaud A.
        • Zhang Y.
        • Dorowhow J.H.
        • et al.
        Trapping of PARP1 and PARP2 by clinical PARP inhibitors.
        Cancer Res. 2012; 72: 5588-5599
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • DeFazio A.
        • Emmanuel C.
        • George J.
        • et al.
        BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.
        J Clin Oncol. 2012; 30: 2654-2663
        • Pal T.
        • Permuth-Wey J.
        • Betts J.A.
        • Krischer J.P.
        • Fiorica J.
        • Arango H.
        • et al.
        BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
        Cancer. 2005; 104: 2807-2816
        • Hennessy B.T.
        • Timms K.M.
        • Carey M.S.
        • Gutin A.
        • Meyer L.A.
        • Flake D.D.
        • et al.
        Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.
        J Clin Oncol. 2010; 28: 3570-3576
        • Audeh M.W.
        • Carmichael J.
        • Penson R.T.
        • Friedlander M.
        • Powell B.
        • Bell-McGuinn K.M.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 245-251
        • Gelmon K.A.
        • Tischkowitz M.
        • Mackay H.
        • Swenerton K.
        • Robidoux A.
        • Tonkin K.
        • et al.
        Olaparib in patients with high grade serous or poorly differentiated ovarian carcinoma or triple negative breast cancer: a phase 2, multicenter, open-label, non-randomized study.
        Lancet Oncol. 2011; 12: 852-861
        • 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
        • Pennington K.P.
        • Swisher E.M.
        Hereditary ovarian cancer: beyond the usual suspects.
        Gynecol Oncol. 2012; 124: 347-353
        • Mateo J.
        • Ong M.
        • Tan D.S.
        • Gonzalex M.A.
        • de Bono J.S.
        Appraising iniparib, the PARP inhibitor that never was-what must we learn?.
        Nat Rev Clin Oncol. 2013; 10: 688-696
        • Patel A.G.
        • De Lorenzo S.B.
        • Flatten K.S.
        • Poirier G.G.
        • Kaufmann S.H.
        Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro.
        Clin Cancer Res. 2012; 18: 1655-1662
        • Kaye S.B.
        • Lubinski J.
        • Matulonis U.
        • Ang J.E.
        • Gourley C.
        • Karlan B.Y.
        • et al.
        Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.
        J Clin Oncol. 2012; 30: 372-379
        • Fong P.C.
        • Yap T.A.
        • Boss D.S.
        • Carden C.P.
        • Mergui-Roelvink M.
        • Gourley C.
        • et al.
        Poly(ADP-ribose) polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
        J Clin Oncol. 2010; 28: 2512-2519
        • Norquist B.
        • Wurz K.A.
        • Pennil C.C.
        • Garcia R.
        • Gross J.
        • Sakai W.
        • et al.
        Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas.
        J Clin Oncol. 2011; 29: 3008-3015
        • Lord C.J.
        • Ashworth A.
        Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
        Nat Med. 2013; 19: 1381-1388
        • 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
        • Bunting S.F.
        • Callén E.
        • Wong N.
        • Chen H.T.
        • Polato F.
        • Gunn A.
        • et al.
        53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.
        Cell. 2010; 141: 243-254
        • Bunting S.F.
        • Callén E.
        • Kozak M.L.
        • Kim J.M.
        • Wong N.
        • Lopez-Contreras A.J.
        • et al.
        BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair.
        Mol Cell. 2012; 46: 125-135
        • Safra T.
        • Borgato L.
        • Nicoletto M.O.
        • Rolnitzky L.
        • Pelles-Avraham S.
        • Geva R.
        • et al.
        BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin.
        Mol Cancer Ther. 2011; 10: 2000-2007
        • Balmana J.
        • Tung N.
        • Isakoff S.J.
        • Grana B.
        • Ryan P.D.
        • Rafi R.
        • et al.
        Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors.
        J Clin Oncol. 2012; 30 ([suppl; abstr 1009])
        • Rajan A.
        • Carter C.A.
        • Kelly R.J.
        • Gutierrez M.
        • Kummar S.
        • Szabo E.
        • et al.
        A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
        Clin Cancer Res. 2012; 18: 2344-2351
        • Lee J.M.
        • Annunziata C.M.
        • Hays J.L.
        • Noonan A.M.
        • Minasian L.M.
        • Zujewski J.
        • et al.
        Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062). DNA Repair and Apoptosis 2514.
        J Clin Oncol. 2013; 31 ([Suppl.; abstr 2514])
        • van der Noll Ruud
        • Ern Ang Joo
        • Agnes Jager S.
        • Marchetti S.
        • Mergui-Roelvink M.
        • DeBono J.S.
        • et al.
        Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors.
        J Clin Oncol. 2013; 31 ([Suppl.; abstr 2579])
        • Oza A.M.
        • Cibula D.
        • Oaknin A.
        • Poole C.J.
        • Mathijssen R.H.J.
        • Sonke G.S.
        • et al.
        Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients with platinum-sensitive recurrent serous ovarian cancer: a randomized, open-label phase II study.
        J Clin Oncol. 2012; 30 ([Suppl.; abstr 5001])
        • Penning T.D.
        • Zhu G.D.
        • Gandhi V.B.
        • Gong J.
        • Liu X.
        • Shi Y.
        • et al.
        Discovery of the poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer.
        J Med Chem. 2009; 52: 514-523
        • Coleman R.
        • Sill M.
        • Aghajanian C.
        • et al.
        A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation — a Gynecologic Oncology Group study.
        in: Society of Gynecologic Oncology Annual Meeting on Women's Cancer. 2013 ([Abstract LBA5])
        • Kummar S.
        • Chen A.
        • Ji J.
        • Zhang Y.
        • Reid J.M.
        • Ames M.
        • et al.
        Phase I study of PARP inhibitor ABT-888 in combination with topotecan in Adults with refractory solid tumors and lymphomas.
        Cancer Res. 2011; 71: 5626-5634
        • LoRusso P.
        • Ji J.
        • Li J.
        • Heilbrun L.K.
        • Shapiro G.
        • Sausville E.A.
        • et al.
        Phase I study of the safety, pharmacokinetics and pharmacodynamics of the poly(ADP-ribose)polymerase (PARP) inhibitor veliparib (ABT-888) in combination with irinotecan (CPT-111) in patients with advanced solid tumors.
        J Clin Oncol. 2011; 29 ([Suppl.: abstract 3000])
        • Tan A.R.
        • Toppmeyer D.
        • Stein M.N.
        • Moss R.A.
        • Gounder M.
        • Lindquist D.C.
        • et al.
        Phase I trial of veliparib (ABT-888), a poly(ADP-ribose)polymerase (PARP) inhibitor in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors.
        J Clin Oncol. 2011; 29 ([Suppl.: abstract 3041])
        • Kummar S.
        • Ji J.
        • Morgan R.
        • Lenz H.J.
        • Puhalla S.L.
        • Belani C.P.
        • et al.
        A Phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
        Clin Cancer Res. 2012; 18: 1726-1734
        • Kummar S.
        • Kinders R.
        • Gutierrez M.E.
        • Rubinstein L.
        • Parchment R.E.
        • Phillips L.R.
        • et al.
        Phase 0 clinical trial of the poly(ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies.
        J Clin Oncol. 2009; 27: 2705-2711
        • Kummar S.
        • Oza A.M.
        • Fleming G.F.
        • Sullivan D.
        • Gandara D.R.
        • Erlichman C.
        • et al.
        Randomized trial of oral cyclophosphamide with or without veliparib, an oral poly (ADP-ribose) polymerase inhibitor, in patients with recurrent BRCA-positive ovarian, or primary peritoneal or high grade serous ovarian cancer.
        J Clin Oncol. 2012; 30 ([Suppl.; abstr 5020])
        • Jones P.
        • Altamura S.
        • Boueres J.
        • Ferrigno F.
        • Fonsi M.
        • Giomini C.
        • et al.
        Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
        J Med Chem. 2009; 52: 7170-7185
        • Sandhu S.K.
        • Schelman W.R.
        • Wilding G.
        • Moreno V.
        • Baird R.D.
        • Miranda S.
        • et al.
        The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.
        Lancet Oncol. 2013; 14: 882-892
        • Ihnen M.
        • zu Eulenburg C.
        • Kolarova T.
        • Qi J.W.
        • Manivong K.
        • Chalukya M.
        • et al.
        Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.
        Mol Cancer Ther. 2013; 12: 1002-1015
        • Shapiro G.
        • Kristeleit R.
        • Middleton M.
        • Burris H.
        • Molife L.R.
        • Evans J.
        • et al.
        Pharmacokinetics of orally administered rucaparib in patients with advanced solid tumors.
        in: Proceedings of AACR/NCI/EORTC targeted therapies meeting. 2013 ([abstract 218])
        • Kristeleit R.
        • Burris H.
        • LoRusso P.
        • Patel M.
        • Giordano H.
        • Evans J.
        • et al.
        Phase I study of continuous oral rucaparib: analysis of patient subgroup with ovarian/peritoneal cancer.
        in: Proceedings from the European Society of Gynecologic Oncology meeting. 2013 ([abstract 124])
        • 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. 2008; 14: 7917-7923
        • Roxburgh P.
        • Molife L.R.
        • Gupta A.
        • Wilson R.
        • Evans J.
        • Cresti N.
        • et al.
        A phase I study of oral rucaparib in combination with carboplatin.
        in: Proceedings from the European Cancer Congress. 2013 ([abstract 824])
        • Coupe N.
        • Roxburgh P.
        • Drew Y.
        • Molife L.R.
        • Wilson R.
        • Spicer J.
        • et al.
        Phase I study of oral or intravenous rucaparib in combination with platinum-containing chemotherapeutic regimens: analysis of patients with ovarian or peritoneal cancers.
        in: Eur Soc of Gyn Onc Proceedings. 2013 ([abstract 155])
        • Shen Y.
        • Rehman F.L.
        • Feng Y.
        • Boshuizen J.
        • Bajrami I.
        • Elliott R.
        • et al.
        BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.
        Clin Cancer Res. 2013; 19: 5003-5015
        • De Bono J.S.
        • Mina L.A.
        • Gonzalez M.
        • Curtin N.J.
        • Wang E.
        • Henshaw J.W.
        • et al.
        First-in-human trial of the novel PARP inhibitor BMN 673 in patients with solid tumors.
        J Clin Oncol. 2013; 31 ([Suppl.; abstr 2580])
        • Tentori L.
        • Lacal P.M.
        • Muzi A.
        • Dorio A.S.
        • Leonetti C.
        • Scarsella M.
        • et al.
        Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis.
        Eur J Cancer. 2007; 43: 2124-2133
        • Bindra R.S.
        • Gibson S.L.
        • Meng A.
        • Westermark U.
        • Jasin M.
        • Pierce A.J.
        • et al.
        Hypoxia-induced down-regulation of BRCA1 expression by E2Fs.
        Cancer Res. 2005; 65: 11597-11604
        • Bindra R.S.
        • Schaffer P.J.
        • Meng A.
        • Woo J.
        • Maseide K.
        • Roth M.E.
        • et al.
        Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
        Mol Cell Biol. 2004; 24: 8504-8518
        • Chan N.
        • Bristow R.G.
        “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair.
        Clin Cancer Res. 2010; 16: 4553-4560
        • Hegan D.C.
        • Lu Y.
        • Stachelek G.C.
        • Crosby M.E.
        • Bindra R.S.
        • Glazer P.M.
        Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130.
        Proc Natl Acad Sci U S A. 2010; 107: 2201-2206
        • Dean E.
        • Middleton M.R.
        • Pwint T.
        • Swaisland H.
        • Carmichael J.
        • Goodege-Kunwar P.
        • et al.
        Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumors.
        Br J Cancer. 2012; 106: 468-474
        • Matulonis U.A.
        • Berlin S.
        • Ivy P.
        • Tyburski K.
        • Krasner C.
        • Zarwan C.
        • et al.
        Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube and peritoneal cancer.
        . 2009; 27: 5601-5606
        • Liu J.F.
        • Tolaney S.M.
        • Birrer M.
        • Fleming G.F.
        • Buss M.K.
        • Dahlberg S.E.
        • et al.
        A phase I trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
        Eur J Cancer. 2013; 49: 2972-2978
        • Kolasa I.K.
        • Rembiszewska A.
        • Felisiak A.
        • Ziolkowska-Seta I.
        • Murawska M.
        • Moes J.
        • et al.
        PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients.
        Cancer Biol Ther. 2009; 8: 21-26
        • Bast Jr., R.C.
        • Hennessy B.
        • Mills G.B.
        The biology of ovarian cancer: new opportunities for translation.
        Nat Rev Cancer. 2009; 9: 415-428
        • Juvekar A.
        • Burga L.N.
        • Hu H.
        • Lunsford E.P.
        • Ibrahim Y.H.
        • Balmana J.
        • et al.
        Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
        Cancer Discov. 2012; 2: 1048-1063
        • Ibrahim Y.H.
        • García-García C.
        • Serra V.
        • He L.
        • Torres-Lockhart K.
        • Prat A.
        • et al.
        PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.
        Cancer Discov. 2012; 2: 1036-1047
        • Murai J.
        • Huang S.Y.
        • Renaud A.
        • Zhang Y.
        • Ji J.
        • Takeda S.
        • et al.
        Stereospecific PARP trapping by BMN673 and comparison with olaparib and rucaparib.
        Mol Cancer Ther. 2014; 13: 433-443