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Using PARP Inhibitors in the Treatment of Patients With Ovarian Cancer

  • Katherine C. Kurnit
  • Robert L. Coleman
  • Shannon N. WestinEmail author
Gynecologic Cancers (LA Cantrell, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gynecologic Cancers

Opinion statement

Use of poly(ADP-ribose) polymerase (PARP) inhibitors has greatly increased over the past 5 years. With several new Food and Drug Administration (FDA) approvals, three PARP inhibitors have entered into standard of care treatment for epithelial ovarian cancer (including ovarian, fallopian tube, and primary peritoneal cancer). Olaparib and rucaparib currently have indications for treatment of recurrent BRCA mutant ovarian cancer. Olaparib, rucaparib, and niraparib all have indications for maintenance therapy in recurrent platinum-sensitive ovarian cancer after response to platinum-based therapy. In our practice, we use both olaparib and rucaparib in the recurrent setting, and all three PARP inhibitors in the maintenance setting. Choice of which PARP inhibitor to use in either setting is largely based upon baseline laboratory values, number of prior therapies, and presence of a BRCA mutation and/or homologous recombination deficiency (HRD). As (HRD) and other biomarker assessments continue to improve, we anticipate being able to better identify which patients might most benefit from PARP inhibitor therapy in the future. The clinically available PARP inhibitors are currently undergoing extensive investigations in clinical trials. Other newer agents such as talazoparib, veliparib, 2X-121, and CEP-9722 are in earlier stages of development. As more FDA-approved indications for PARP inhibitor therapy in ovarian cancer become available, we anticipate the decision of which PARP inhibitor to use will become increasingly complex.

Keywords

Ovarian cancer PARP inhibitors Targeted therapy Treatment Maintenance 

Notes

Funding Source

This study is supported by NIH T32 Training Grant (5 T32 CA101642 02) NIH SPORE in Ovarian Cancer (NIH 2P50 CA109298), NIH MD Anderson Cancer Center Support Grant (P30CA016672), and Judy Reis/Al Pisani Ovarian Cancer Research Fund, CPRIT RP120214; SNW is supported by the Andrew Sabin Family Fellowship; RLC is supported by the Ann Rife Cox Chair in Gynecology.

Compliance with Ethical Standards

Conflict of Interest

Katherine Kurnit declares that she has no conflict of interest.

Robert L. Coleman has received research funding through grants from the National Institutes of Health (NIH), the Gateway Fondation, and the V Foundation; has also received research support from AstraZeneca, Merck, Clovis, Genmab, Roche/Genentech, and Janssen; and has received compensation from AstraZeneca, Tesaro, Medivation, Clovis, GamaMabs, Genmab, Roche/Genentech, Janssen, Agenus, Regeneron, and OncoQuest for service as a consultant.

Shannon N. Westin has received research funding through grants from the NIH and the Andrew Sabin Family Fellowship; has also received research support from AstraZeneca, Tesaro, and Cotinga Pharmaceuticals; and has received compensation from AstraZeneca, Merck, Tesaro, Medivation, Clovis, Casdin Capital, Ovation, and Roche/Genentech 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.

References and Recommended Reading

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

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.  https://doi.org/10.3322/caac.21442.CrossRefGoogle Scholar
  2. 2.
    Network NCC. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 2.2018). https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed 29 June 2018.
  3. 3.
    Pommier Y, O’Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med. 2016;8:362):362 ps17.  https://doi.org/10.1126/scitranslmed.aaf9246.CrossRefGoogle Scholar
  4. 4.
    Ronson GE, Piberger AL, Higgs MR, Olsen AL, Stewart GS, McHugh PJ, et al. PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation. Nat Commun. 2018;9(1):746.  https://doi.org/10.1038/s41467-018-03159-2.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33(12):1397–406.  https://doi.org/10.1200/jco.2014.58.8848.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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.  https://doi.org/10.1158/0008-5472.can-12-2753.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dudas A, Chovanec M. DNA double-strand break repair by homologous recombination. Mutat Res. 2004;566(2):131–67.  https://doi.org/10.1016/j.mrrev.2003.07.001.CrossRefPubMedGoogle Scholar
  8. 8.
    McCabe N, Turner NC, Lord CJ, 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(16):8109–15.  https://doi.org/10.1158/0008-5472.can-06-0140.CrossRefPubMedGoogle Scholar
  9. 9.
    Lheureux S, Lai Z, Dougherty BA, Runswick S, Hodgson DR, Timms KM, et al. Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: clinical and molecular characterization. Clin Cancer Res. 2017;23(15):4086–94.  https://doi.org/10.1158/1078-0432.ccr-16-2615.CrossRefPubMedGoogle Scholar
  10. 10.
    Ledermann JA, Drew Y, Kristeleit RS. Homologous recombination deficiency and ovarian cancer. Eur J Cancer (Oxford, England: 1990). 2016;60:49–58.  https://doi.org/10.1016/j.ejca.2016.03.005.CrossRefGoogle Scholar
  11. 11.
    The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15.  https://doi.org/10.1038/nature10166.
  12. 12.
    Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germ line BRCA1/2 mutation. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(3):244–50.  https://doi.org/10.1200/jco.2014.56.2728.CrossRefGoogle Scholar
  13. 13.
    Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, et al. FDA Approval summary: olaparib monotherapy in patients with deleterious germ line BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257–61.  https://doi.org/10.1158/1078-0432.ccr-15-0887.CrossRefPubMedGoogle Scholar
  14. 14.
    Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germ line BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017;23(15):4095–106.  https://doi.org/10.1158/1078-0432.ccr-16-2796.CrossRefPubMedGoogle Scholar
  15. 15.
    Swisher EM, Lin KK, Oza AM, Scott CL, 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(1):75–87.  https://doi.org/10.1016/s1470-2045(16)30559-9.CrossRefPubMedGoogle Scholar
  16. 16.
    • Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germ line or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147(2):267–75.  https://doi.org/10.1016/j.ygyno.2017.08.022 The integrated analysis of two phase II studies of rucaparib in recurrent ovarian cancer patients with BRCA mutations. This provided the basis for the rucaparib FDA approval. CrossRefPubMedGoogle Scholar
  17. 17.
    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.  https://doi.org/10.1016/s1470-2045(13)70240-7.CrossRefPubMedGoogle Scholar
  18. 18.
    Moore KN, Secord AA, Geller MA, Miller DS, Cloven NG, Fleming GF, et al. QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients (pts) with relapsed ovarian cancer (ROC) who have received ≥ 3 prior chemotherapy regimens. J Clin Oncol. 2018;36(15_suppl):5514.Google Scholar
  19. 19.
    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 germ line BRCA1 or BRCA2 mutation—an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137(3):386–91.  https://doi.org/10.1016/j.ygyno.2015.03.042.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    •• Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64.  https://doi.org/10.1056/NEJMoa1611310 The phase III study of niraparib in platinum-sensitive, recurrent ovarian cancer patients. This study served as the basis for the FDA approval. CrossRefPubMedGoogle Scholar
  21. 21.
    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.  https://doi.org/10.1056/NEJMoa1105535.CrossRefPubMedGoogle Scholar
  22. 22.
    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(8):852–61.  https://doi.org/10.1016/s1470-2045(14)70228-1.CrossRefPubMedGoogle Scholar
  23. 23.
    Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016;17(11):1579–89.  https://doi.org/10.1016/s1470-2045(16)30376-x.CrossRefPubMedGoogle Scholar
  24. 24.
    Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer. Br J Cancer. 2016;115(11):1313–20.  https://doi.org/10.1038/bjc.2016.348.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    •• Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, 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(9):1274–84.  https://doi.org/10.1016/s1470-2045(17)30469-2 The phase III study of olaparib in platinum-sensitive, recurrent ovarian cancer patients with BRCA mutations. This study served as the basis for the FDA approval. CrossRefPubMedGoogle Scholar
  26. 26.
    •• Coleman RL, Oza AM, 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 (London, England). 2017;390(10106):1949–61.  https://doi.org/10.1016/s0140-6736(17)32440-6 The phase III study of rucaparib in platinum-sensitive, recurrent ovarian cancer patients. This study served as the basis for the FDA approval. CrossRefGoogle Scholar
  27. 27.
    Bell-McGuinn KM, 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(15_suppl):5507.Google Scholar
  28. 28.
    Nishio S, Takekuma M, Takeuchi S, Kawano K, Tsuda N, Tasaki K, et al. Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer. Cancer Sci. 2017;108(11):2213–20.  https://doi.org/10.1111/cas.13381.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Moore KN, DiSilvestro P, Lowe ES, Garnett S, Pujade-Lauraine E. SOLO1 and SOLO2: randomized phase III trials of olaparib in patients (pts) with ovarian cancer and a BRCA1/2 mutation (BRCAm). J Clin Oncol. 2014;32(15_suppl):TPS5616-TPS.  https://doi.org/10.1200/jco.2014.32.15_suppl.tps5616.CrossRefGoogle Scholar
  30. 30.
    Del Conte G, Sessa C, von Moos R, Vigano L, Digena T, Locatelli A, et al. Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer. 2014;111(4):651–9.  https://doi.org/10.1038/bjc.2014.345.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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.  https://doi.org/10.1158/1078-0432.ccr-14-2565.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wahner Hendrickson AE, Menefee ME, Hartmann LC, Long HJ, Northfelt DW, Reid JM, et al. A phase I clinical trial of the poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors. Clin Cancer Res. 2018;24(4):744–52.  https://doi.org/10.1158/1078-0432.ccr-17-1590.CrossRefPubMedGoogle Scholar
  33. 33.
    • 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.  https://doi.org/10.1016/s1470-2045(14)71135-0 One of the first phase II trials evaluating the combination of a PARP inhibitor with standard of care chemotherapy. CrossRefPubMedGoogle Scholar
  34. 34.
    Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, et al. Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women’s cancer. Clin Cancer Res. 2017;23(6):1397–406.  https://doi.org/10.1158/1078-0432.ccr-16-1546.CrossRefPubMedGoogle Scholar
  35. 35.
    Matulonis UA, Wulf GM, Barry WT, Birrer M, Westin SN, Farooq S, et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol. 2017;28(3):512–8.  https://doi.org/10.1093/annonc/mdw672.CrossRefPubMedGoogle Scholar
  36. 36.
    Westin S, Litton J, Williams R, Soliman P, Frumovitz M, Schmeler K, et al. 391P Phase I expansion of olaparib (PARP inhibitor) and AZD5363 (AKT inhibitor) in recurrent ovarian, endometrial and triple negative breast cancer. Ann Oncol. 2017;28(suppl_5):mdx367.025-mdx367.025.  https://doi.org/10.1093/annonc/mdx367.025.CrossRefGoogle Scholar
  37. 37.
    Westin SN, Litton JK, Williams RA, Shepherd CJ, Brugger W, Pease EJ, et al. Phase I trial of olaparib (PARP inhibitor) and vistusertib (mTORC1/2 inhibitor) in recurrent endometrial, ovarian and triple negative breast cancer. J Clin Oncol. 2018;36(15_suppl):5504.  https://doi.org/10.1200/JCO.2018.36.15_suppl.5504.CrossRefGoogle Scholar
  38. 38.
    • 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. The Lancet Oncology. 2014;15(11):1207–14.  https://doi.org/10.1016/s1470-2045(14)70391-2 One of the most promising published clinical trials of the combination of a PARP inhibitor and a novel agent. The combination had more notable improvement in efficacy in BRCA wild type patients. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu JF, Barry WT, Birrer MJ, J-m L, Buckanovich RJ, Fleming GF, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2017;35(15_suppl):5535.  https://doi.org/10.1200/JCO.2017.35.15_suppl.5535.CrossRefGoogle Scholar
  40. 40.
    Konstantinopoulos PA, Waggoner SE, Vidal GA, Mita MM, Fleming GF, Holloway RW, et al. TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort. J Clin Oncol. 2018;36(15_suppl):106.Google Scholar
  41. 41.
    Drew Y, De Jonge M, Hong SH, Park YH, Wolfer A, Brown J et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germ line BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 26, 2018; New Orleans, Louisiana2018.Google Scholar
  42. 42.
    Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1–3 inhibitor cediranib in women’s cancers: a dose-escalation, phase I study. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(19):2193–202.  https://doi.org/10.1200/jco.2016.72.1340.CrossRefGoogle Scholar
  43. 43.
    Domchek S, Bang YJ, Coukos G, Kobayashi K, Baker N, McMurtry E, et al. MEDIOLA: A phase I/II, open-label trial of olaparib in combination with durvalumab (MEDI4736) in patients (pts) with advanced solid tumours. Annals of Oncology. 2016;27(suppl_6):1103TiP-TiP.  https://doi.org/10.1093/annonc/mdw378.56.CrossRefGoogle Scholar
  44. 44.
    Sun C, Fang Y, Yin J, Chen J, Ju Z, Zhang D, et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci Transl Med. 2017;9(392).  https://doi.org/10.1126/scitranslmed.aal5148.
  45. 45.
    Kaufmann SH, Hendrickson AEW, Harrell MI, Menefee ME, Tanner EJ, Mutch DG et al. Abstract IS04: PARP inhibitor combinations for the treatment of ovarian cancer. Clin Cancer Res. 2017;23(11_Suppl):IS04.Google Scholar
  46. 46.
    Wilson AJ, Thompson J, Osman A, Saskowski J, Khabele DK. Abstract 5056: The bromodomain inhibitor JQ1 sensitizes homologous recombination proficient ovarian cancer cells to the PARP inhibitor olaparib. Cancer Res. 2017;77(13_Suppl):5056.Google Scholar
  47. 47.
    Brill E, Yokoyama T, Nair J, Yu M, Ahn YR, Lee JM. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer. Oncotarget. 2017;8(67):111026–40.  https://doi.org/10.18632/oncotarget.22195.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Michels J, Vitale I, Saparbaev M, Castedo M, Kroemer G. Predictive biomarkers for cancer therapy with PARP inhibitors. Oncogene. 2014;33(30):3894–907.  https://doi.org/10.1038/onc.2013.352.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Katherine C. Kurnit
    • 1
  • Robert L. Coleman
    • 1
  • Shannon N. Westin
    • 1
    Email author
  1. 1.Department of Gynecologic Oncology and Reproductive MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA

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