Skip to main content

Advertisement

Log in

What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?

  • Gynecologic Cancers (NS Reed, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26(8):882–93. eng.

    Article  CAS  PubMed  Google Scholar 

  2. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7. eng.

    Article  CAS  PubMed  Google Scholar 

  3. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21. eng.

    Article  CAS  PubMed  Google Scholar 

  4. Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. Pubmed Central PMCID: 3163504. This publication describes findings from analyzing messenger RNA expression, microRNA expression, promoter methylation, and DNA copy number in 489 HGSOCs and exon sequencing in 316 of these samples. Importantly, it describes that ∼50% of HGSOC have a molecular alteration in genes involved in HR and may therefore have increased susceptibility to PARP inhibition.

  5. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137–54. Pubmed Central PMCID: 4631624.

    Article  CAS  PubMed  Google Scholar 

  6. Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33(12):1397–406. Pubmed Central PMCID: 4517072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110–20.

    Article  CAS  PubMed  Google Scholar 

  8. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99. Pubmed Central PMCID: 3528345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Patel AG, Sarkaria JN, Kaufmann SH. 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(8):3406–11. Pubmed Central PMCID: 3044391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34. eng.

    Article  CAS  PubMed  Google Scholar 

  11. Fong PC, Yap TA, Boss DS, Carden CP, 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(15):2512–9.

    Article  CAS  PubMed  Google Scholar 

  12. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, 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(9737):245–51. eng.

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50. This publication describes the activity of olaparib monotherapy in patients with germline BRCA1/2 mutations, including ovarian cancer, where the response rate was 31%. The results of this trial served as the basis for US FDA approval of olaparib in 2014.

  14. Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199–203.

    Article  CAS  PubMed  Google Scholar 

  15. Coleman RL, Sill MW, Bell-McGuinn K, Aghajanian C, Gray HJ, Tewari KS, 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—an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137(3):386–91. Pubmed Central PMCID: 4447525.

    Article  CAS  PubMed  Google Scholar 

  16. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, 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(9):882–92.

    Article  CAS  PubMed  Google Scholar 

  17. Kristeleit R, Shapira-Frommer R, Burris H, Patel MR, Lorusso P, Oza A, et al. Phase 1/2 study of oral rucaparib: updated phase 1 and preliminary phase 2 results. Ann Oncol. 2014;25 suppl 4:iv305–iv26. Abstract, ESMO 2014.

    Google Scholar 

  18. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, 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(4):372–9.

    Article  CAS  PubMed  Google Scholar 

  19. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, 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(3):764–75. Pubmed Central PMCID: 3944197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61. eng.

    Article  CAS  PubMed  Google Scholar 

  21. Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010;28(22):3555–61. Pubmed Central PMCID: 2917311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012;107(10):1776–82. Pubmed Central PMCID: 3493866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2012;2(4):366–75. Pubmed Central PMCID: 3806629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012;72(21):5454–62.

    Article  CAS  PubMed  Google Scholar 

  25. Kristeleit R, Swisher EM, Oza A, Coleman RL, Scott C, Konecny G, et al. Final results of ARIEL2 (Part 1): a phase 2 trial to prospectively identify ovarian cancer (OC) responders to rucaparib using tumor genetic analysis. Presented at ECCO 2015. 2015.

  26. Ledermann J, 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(15):1382–92. This randomized Phase 2 trial observed significant improvement in PFS study-wide and in pre-defined subgroups of platinum-sensitive ovarian cancer who received olaparib maintenance following platinum therapy compared to placebo.

  27. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852. This pre-planned subset analysis of BRCA-mutated (tumor or somatic) tumors within the randomized Phase 2 trial described in Ledermann et al. in 2012 (previous reference) reported marked improvement in PFS (11.2 mos vs. 4.3 mos) for women receiving olaparib maintenance therapy versus placebo. These findings form the basis for the EMA approval of olaparib in 2014.

  28. Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst. 2014;106(6):dju089. Pubmed Central PMCID: 4049120.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2015;16(1):87–97.

    Article  CAS  PubMed  Google Scholar 

  30. Kummar S, Oza AM, Fleming GF, Sullivan DM, Gandara DR, Naughton MJ, et al. Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer. Clin Cancer Res. 2015;21(7):1574–82. Pubmed Central PMCID: 4383665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bell-McGuinn K, Brady WE, Schilder RJ, Fracasso PM, Moore KN, Walker JL, et al. A phase I study of continuous veliparib in combination with IV carboplatin/paclitaxel or IV/IP paclitaxel/cisplatin and bevacizumab in newly diagnosed patients with previously untreated epithelial ovarian, fallopian tube, or primary peritoneal cancer: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2015;33(suppl; abstr 5507):Presented at ASCO 2015.

    Google Scholar 

  32. Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, 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(11):1207–14. Pubmed Central PMCID: 4294183. This Phase 2 study demonstrated significant improvement in PFS and response rates in women with recurrent platinum-sensitive ovarian cancer receiving a combination of cediranib and olaparib compared to olaparib alone, with demonstrated activity of the combination in patients both with and without a known BRCA mutation. This trial suggests that combining PARPi’s with other targeted agents may result in synergistic effects and broaden the population of ovarian cancer patients in whom PARPi-based therapies might be pursued.

  33. Hirte H, Lheureux S, Fleming GF, Sugimoto A, Morgan R, Biagi J, et al. A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia. Gynecol Oncol. 2015;138(1):55–61.

    Article  CAS  PubMed  Google Scholar 

  34. Matulonis UA, 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. J Clin Oncol. 2009;27(33):5601–6. eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, et al. A Phase 1 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(14):2972–8. Pubmed Central PMCID: 3956307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, et al. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005;65(24):11597–604. eng.

    Article  CAS  PubMed  Google Scholar 

  37. Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol. 2004;24(19):8504–18. eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lim JJ, Yang K, Taylor-Harding B, Wiedemeyer WR, Buckanovich RJ. VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. Neoplasia. 2014;16(4):343–53. e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ibrahim YH, Garcia-Garcia 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(11):1036–47.

    Article  CAS  PubMed  Google Scholar 

  40. Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, 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(11):1048–63. Pubmed Central PMCID: 3733368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Matulonis U, Wulf GM, Barry WT, Birrer M, Westin S, Spagnoletti T, et al. Phase I of oral BKM120 or BYL719 and olaparib for high-grade serous ovarian cancer or triple-negative breast cancer: final results of the BKM120 plus olaparib cohort. Cancer Res. 2015;75(Abst CT324):Presented at AACR 2015.

    Google Scholar 

  42. Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016 Feb 9 doi:10.18632/oncotarget.7277.

  43. Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463(4):551–6.

    Article  CAS  PubMed  Google Scholar 

  44. Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA, et al. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immun Res. 2015;3(11):1257–68.

    Article  CAS  Google Scholar 

  45. Johnson N, Li YC, Walton ZE, Cheng KA, Li D, Rodig SJ, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med. 2011;17(7):875–82. Pubmed Central PMCID: 3272302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Konstantinopoulos PA, Wilson AJ, Saskowski J, Wass E, Khabele D. Suberoylanilide hydroxamic acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer. Gynecol Oncol. 2014;133(3):599–606. Pubmed Central PMCID: 4347923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Choi YE, Battelli C, Watson J, Liu J, Curtis J, Morse AN, et al. Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells. Oncotarget. 2014;5(9):2678–87. Pubmed Central PMCID: 4058036.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joyce F. Liu.

Ethics declarations

Conflict of Interest

Joyce Liu has received compensation from AstraZeneca and Genentech/Roche for service as a consultant.

Ursula A. Matulonis has received compensation from Genentech/Roche, Pfizer, AstraZeneca, and Merck for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Gynecologic Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J.F., Matulonis, U.A. What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?. Curr Oncol Rep 18, 29 (2016). https://doi.org/10.1007/s11912-016-0515-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-016-0515-z

Keywords

Navigation