Skip to main content

Advertisement

SpringerLink
Log in

Emerging Therapies in the Management of High-Grade Serous Ovarian Carcinoma: a Focus on PARP Inhibitors

  • Gynecologic Oncology (A Fader, Section Editor)
  • Published:
Current Obstetrics and Gynecology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The aims of this review are to describe key clinical trials that led to Federal Drug Administration (FDA) approval of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment, contextualize current indications, and to present future perspectives on the use of PARP inhibitors in this setting.

Recent Findings

Since 2014, the FDA has approved three PARP inhibitors for the treatment of relapsed ovarian cancer, initially for patients with BRCA mutations and more recently, for a broader patient population.

Summary

High-grade serous ovarian carcinomas (HGSOC) account for more than 70% of epithelial ovarian cancers. DNA repair is frequently defective in these cancers, and homologous recombination pathway defects are present in approximately 50% of cases. The inhibition of PARP enzymes is a potential synthetic lethal therapeutic strategy for cancers harboring DNA repair defects, including ovarian cancers arising in the presence of BRCA mutations or other forms of homologous recombination deficiency. PARP inhibitors are now an exciting option for the treatment of patients with advanced ovarian cancer. Herein, this topic will be further explored.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  2. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519–29.

    Article  CAS  PubMed  Google Scholar 

  3. Cobb LP, Gaillard S, Wang Y, Shih Ie M, Secord AA. Adenocarcinoma of Mullerian origin: review of pathogenesis, molecular biology, and emerging treatment paradigms. Gynecol Oncol Res Pract. 2015;2:1.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Karlan BY, Alvarez RD, Strauss JF 3rd. Evolving paradigms in research and care in ovarian cancers. Obstet Gynecol. 2016;128(4):771–4.

    Article  PubMed  Google Scholar 

  5. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15.

  6. •• 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. Farmer H et al. and Bryant HE et al. were the first to demonstrate synthetic lethality of PARP inhibitors in BRCA deficiency.

    Article  CAS  PubMed  Google Scholar 

  7. •• 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. Farmer H et al. and Bryant HE et al. were the first to demonstrate synthetic lethality of PARP inhibitors in BRCA deficiency.

    Article  CAS  PubMed  Google Scholar 

  8. Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115(10):1157–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell. 2013;23(5):693–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. •• 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. Proof-of-concept study that shows safety and efficacy of olaparib in BRCA mutation-associated ovarian cancer.

    Article  CAS  PubMed  Google Scholar 

  14. Kaye SB, Poole CJ, Danska-Bidzinska A, Gianni L, Del Conte G, Gorbunova V, et al. A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer. Ann Oncol. 2013;24(1):145–52.

    Article  CAS  PubMed  Google Scholar 

  15. •• 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. First study to demonstrate activity of a PARP inhibitor in patients with ovarian cancer without germline BRCA mutations.

    Article  CAS  PubMed  Google Scholar 

  16. •• 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 study showed prolonged tumor responses with olaparib in BRCA mutation associated platinum-resistant, heavily pretreated ovarian cancer.

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. • Shapira-Frommer ROA, Domchek SM, et al. A phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Eur J Cancer. 2015;51:S545. Study demonstrating robust antitumor activity of rucaparib in heavily pretreated ovarian cancer with BRCA mutations.

    Article  Google Scholar 

  19. •• 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. Phase II study that embased FDA approval of rucaparib for ovarian cancer treatment and proposed a tumor-based approach to select patients who would benefit from treatment.

    Article  CAS  PubMed  Google Scholar 

  20. • 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. Single-agent activity of veliparib was demonstrated in BRCAm relapsed ovarian cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. This randomized study shows improved PFS in recurrent, platinum-sensitive ovarian cancer treated with olaparib maintenance.

    Article  CAS  PubMed  Google Scholar 

  22. •• 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. This study showed progression-free survival improvement with niraparib maintenance for recurrent, platinum-sensitive ovarian cancer, regardless of BRCA status.

    Article  CAS  PubMed  Google Scholar 

  23. •• Pujade-Lauraine E, Ledermann J, Penson RT, Oza AM, Korach J, Huzarski T, et al. Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: results from the phase III SOLO2 study. Society of Gynecologic Oncology annual meeting on Women’s Cancer (SGO); National Harbor, Maryland.2017. First phase III trial of olaparib as maintenance treatment in recurrent, platinum-sensitive, BRCAm ovarian cancer, which confirmed a PFS benefit.

  24. •• 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. First study to demonstrate a PFS benefit with the combination of an anti-angiogenic and a PARP inhibitor for platinum-sensitive ovarian cancer treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. • 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. First study to show antitumor activity of PARP inhibitors in patients with BRCA mutation-associated tumors.

    Article  CAS  PubMed  Google Scholar 

  26. • 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. This study shows correlation between PARP inhibitor activity and platinum sensitivity in patients with BRCA mutation-associated tumors.

    Article  CAS  PubMed  Google Scholar 

  27. Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257–61.

    Article  CAS  PubMed  Google Scholar 

  28. •• 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. This study shows that patients with platinum-sensitive ovarian cancer and a BRCA mutations derive greatest benefit with olaparib maintenance.

    Article  CAS  PubMed  Google Scholar 

  29. European Medicines Agency. 2014. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003726/WC500176336.pdf.

  30. Federal Drug Administration. 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/206162Orig1s000ltr.pdf.

  31. •• 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. Final overall survival analysis of a trial of olaparib maintenance in patients with recurrent platinum-sensitive ovarian cancer and shows a survival advantage for BRCAm patients.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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(12):e21.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso PM, Patel M, et al. A phase I-II study of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017;

  35. Federal Drug Administration. 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/209115orig1s000ltr.pdf.

  36. 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 

  37. Puhalla SL, Beumer JH, Pahuja S. Final results of a phase 1 study of single-agent veliparib in patient with either BRCA1/2-mutated cancer, platinum-refractory ovarian, or basal-like breast cancer. J Clin Oncol. 2014;32:5s. (Abstract 2570)

    Google Scholar 

  38. Shen Y, Rehman FL, 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(18):5003–15.

    Article  CAS  PubMed  Google Scholar 

  39. Wainberg ZA, Hecht JR, Konecny GE, Goldman JW, Sadeghi S, Chmielowski B, et al. Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozolomide or irinotecan in patients with advanced malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res. 2016;76(14 Suppl):abstract CT011.

  40. de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 2017;7(6):620–9.

  41. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180–6.

    Article  CAS  PubMed  Google Scholar 

  42. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165–71.

    Article  CAS  PubMed  Google Scholar 

  43. • 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. This study showed increased antitumor activity with the combination of an anti-angiogenic and a PARP inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clarke B, Tinker AV, Lee CH, Subramanian S, van de Rijn M, Turbin D, et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009;22(3):393–402.

    Article  CAS  PubMed  Google Scholar 

  45. McAlpine JN, Porter H, Kobel M, Nelson BH, Prentice LM, Kalloger SE, et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol. 2012;25(5):740–50.

    Article  CAS  PubMed  Google Scholar 

  46. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 Immunol Res. 2015;3(11):1257–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kummar S, Ji J, Morgan R, Lenz HJ, Puhalla SL, Belani CP, 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(6):1726–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. LoRusso PM, Li J, Burger A, Heilbrun LK, Sausville EA, Boerner SA, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) in combination with irinotecan in patients with advanced solid tumors. Clin Cancer Res. 2016;22(13):3227–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tan AR, Toppmeyer D, Stein MN, Moss RA, Gounder M, Lindquist DC, 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;29:3041. (Suppl.: abstract 3041)

    Article  Google Scholar 

  51. Reiss KA, Herman JM, Armstrong D, Zahurak M, Fyles A, Brade A, et al. A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers. Gynecol Oncol. 2017;144(3):486–90.

    Article  CAS  PubMed  Google Scholar 

  52. Reiss KA, Herman JM, Zahurak M, Brade A, Dawson LA, Scardina A, et al. A phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis. Clin Cancer Res. 2015;21(1):68–76.

    Article  CAS  PubMed  Google Scholar 

  53. Bell-McGuinn KM, Brady WE, Schilder RJ, Fracasso PM, Moore KM, 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;33:5507. (Abstract 5507)

    Google Scholar 

  54. Landrum LM, Brady WE, Armstrong DK, Moore KN, DiSilvestro PA, O'Malley DM, et al. A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2016;140(2):204–9.

    Article  CAS  PubMed  Google Scholar 

  55. Konner JA, Boucicaut NN, O’Cearbhaill RE. A phase I dose-escalation study of intraperitoneal (IP) cisplatin, IV/IP paclitaxel, IV bevacizumab, and oral olaparib for newly diagnosed adnexal carcinoma. J Clin Oncol. 2017;35 (suppl; abstr 5572).

  56. 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.

Download references

Author information

Authors and Affiliations

  1. Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Karime Kalil Machado & Stéphanie L. Gaillard

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., CRB1-154, Baltimore, MD, 21287, USA

    Stéphanie L. Gaillard

Authors
  1. Karime Kalil Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stéphanie L. Gaillard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stéphanie L. Gaillard.

Ethics declarations

Conflict of Interest

Karime Kalil Machado declares that she has no conflict of interest.

Stéphanie L. Gaillard has received grants and personal fees from Genentech, PharmaMar, and Merck and grants from Tetralogic, Bristol Myers Squibb, and Gradalis. Dr. Gaillard has also received personal fees and non-financial support from Pfizer, personal fees from Tesaro, and a patent application No. 62/457,759, entitled “Lasofoxifene Treatment of Breast Cancer” licensed to Sermonix.

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 Oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Machado, K.K., Gaillard, S.L. Emerging Therapies in the Management of High-Grade Serous Ovarian Carcinoma: a Focus on PARP Inhibitors. Curr Obstet Gynecol Rep 6, 207–218 (2017). https://doi.org/10.1007/s13669-017-0215-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13669-017-0215-1

Keywords

Search

Navigation