Download PDF
CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2020; 41(02): 173-181
DOI: 10.4103/ijmpo.ijmpo_2_20
Review Article

Upfront Maintenance Poly(Adenosine Diphosphate Ribose) Polymerase Inhibitors in Ovarian Cancer: A Ray of Hope or Just a Mirage!

Avinash Pandey
Department of Medical Oncology, State Cancer Institute, IGIMS, Patna, Bihar
,
Joydeep Ghosh
Consultant, Medical Oncologist, Tata Medical Center, Kolkata, West Bengal
› Author Affiliations Financial support and sponsorship Nil.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Poly(adenosine diphosphate ribose) polymerase inhibitors (PARPis), when used in patients harboring tumor with homologous recombination deficiency, with or without BRCA mutation, have shown favorable outcomes in relapsed, advanced metastatic breast and ovarian cancers. Olaparib, niraparib, and rucaparib have been approved as maintenance therapy in platinum-sensitive, relapsed, high-grade epithelial ovarian cancer (EOC) responsive to platinum doublet. Olaparib and rucaparib as monotherapy are also indicated in patients who have progressed on three or more lines of chemotherapy, irrespective of platinum sensitivity, in germline or somatic BRCA 1/2-mutated, PARPi-naive patients. Recently, four large multicentric, international Phase III randomized clinical trials have reported outcomes of PARPi in first-line advanced EOC as maintenance therapy either alone or in combination with bevacizumab. Previously bevacizumab, pazopanib, nindetanib, or maintenance chemotherapy in first-line setting has resulted in modest improvements in progression free survival, albeit with significant toxicities and poor cost-effectiveness. We offer in this review to dissect the data pertaining to randomized clinical trials of PARPi use as maintenance therapy in upfront EOCs and ruminate about its role in the contemporary management of ovarian cancers.

Keywords

Epithelial ovarian cancer - maintenance therapy - poly (adenosine diphosphate ribose) polymerase inhibitors


Publication History

Received: 07 January 2020

Accepted: 02 February 2020

Article published online:
23 May 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108
    CrossrefPubMedGoogle Scholar
  • 2 Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N. et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943-53
    CrossrefPubMedGoogle Scholar
  • 3 Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA. et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996; 335: 1950-5
    CrossrefPubMedGoogle Scholar
  • 4 Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S. et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34-43
    CrossrefPubMedGoogle Scholar
  • 5 Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S. et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396-405
    CrossrefPubMedGoogle Scholar
  • 6 Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E. et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): A randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020-6
    CrossrefPubMedGoogle Scholar
  • 7 Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H. et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473-83
    CrossrefPubMedGoogle Scholar
  • 8 Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G. et al. Aphase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484-96
    CrossrefPubMedGoogle Scholar
  • 9 Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E. et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16: 928-36
    CrossrefPubMedGoogle Scholar
  • 10 du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M. et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 2014; 32: 3374-82
    CrossrefPubMedGoogle Scholar
  • 11 Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018; 379: 2495-505
    CrossrefPubMedGoogle Scholar
  • 12 Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M. et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 2019; 381: 2403-15
    CrossrefPubMedGoogle Scholar
  • 13 González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR. et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019; 381: 2391-402
    CrossrefPubMedGoogle Scholar
  • 14 Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martin A, Sevelda P. et al. Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care. Ann Oncol 2017; 30(Suppl 5): v851-934
    Google Scholar
  • 15 Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib Plus Bevacizumab as Maintenance Therapy in Patients with Newly Diagnosed, Advanced Ovarian Cancer Treated with Platinum-based Chemotherapy Plus Bevacizumab. https://oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/Phase-III-PAOLA-1-ENGOT-ov25-trial-Olaparib-plus-bevacizumab-bev-as-maintenance-therapy-in-patients-pts-with-newly-diagnosed-advanced-ovarian-cancer-OC-treated-with-platinum-based-chemotherapy-PCh-plus-bev Available from: [Last accessed on 2020 Jan 05]
    Google Scholar
  • 16 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: 123-34
    CrossrefPubMedGoogle Scholar
  • 17 O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell 2015; 60: 547-60
    CrossrefPubMedGoogle Scholar
  • 18 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: 8109-15
    CrossrefPubMedGoogle Scholar
  • 19 Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008; 105: 17079-84
    CrossrefPubMedGoogle Scholar
  • 20 Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-50
    CrossrefPubMedGoogle Scholar
  • 21 Matulonis UA, Penson RT, Domchek SM, Kaufman B, Shapira-Frommer R, Audeh MW. et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: A multistudy analysis of response rates and safety. Ann Oncol 2016; 27: 1013-9
    CrossrefPubMedGoogle Scholar
  • 22 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: 1274-84
    CrossrefPubMedGoogle Scholar
  • 23 Hinde S, Epstein D, Cook A, Embleton A, Perren T, Sculpher M. et al. The cost-effectiveness of bevacizumab in advanced ovarian cancer using evidence from the ICON7 trial. Value Health 2016; 19: 431-9
    CrossrefPubMedGoogle Scholar
  • 24 du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N. et al. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2016; 17: 78-89
    CrossrefPubMedGoogle Scholar
  • 25 Norquist BS, Brady MF, Harrell MI, Walsh T, Lee MK, Gulsuner SI. et al. Mutations in homologous recombination genes and response to treatment in GOG 218: An NRG oncology study. Gynecol Oncol 2016; 141: 2
    CrossrefPubMedGoogle Scholar
  • 26 Harter P, Johnson T, Berton-Rigaud D, Park SY, Friedlander M, Del Campo JM. et al. BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study. Gynecol Oncol 2016; 140: 443-9
    CrossrefPubMedGoogle Scholar
  • 27 Rohit K, Gupta S, Rajappa SJ, Advani SH, Agarwal A, Aggarwal S. et al. A non-interventional, multicenter study to assess prevalence of BRCA1 and BRCA2 mutation among ovarian, primary peritoneal, and fallopian tube cancer patients in India. J Clin Oncol 2019; 37 (Suppl. 15) e13073
    CrossrefGoogle Scholar
  • 28 Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S. et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: Prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat 2018; 170: 189-96
    CrossrefPubMedGoogle Scholar
  • 29 Mannan AU, Singh J, Lakshmikeshava R, Thota N, Singh S, Sowmya TS. et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: Implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet 2016; 61: 515-22
    CrossrefPubMedGoogle Scholar
  • 30 Valarmathi MT, Sawhney M, Deo SS, Shukla NK, Das SN. Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families. Hum Mutat 2004; 23: 205
    CrossrefPubMedGoogle Scholar
  • 31 Sharma S, Rajaram S, Sharma T, Goel N, Agarwal S, Banerjee BD. et al. Role of BRCA1 and BRCA2 gene mutations in epithelial ovarian cancer in Indian population: A pilot study. Int J Biochem Mol Biol 2014; 5: 1-0
    PubMedGoogle Scholar
  • 32 Matthew WK, Becker M, Neff C, Abkevich V, Jones JT, Hou X, Wang Y. et al. Use of homologous recombination deficiency (HRD) score to enrich for niraparib sensitive high grade ovarian tumors. J Clin Oncol 2015; 33 (Suppl. 15) 5532
    CrossrefGoogle Scholar
  • 33 Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 2016; 22: 3764-73
    CrossrefPubMedGoogle Scholar