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Poly (ADP-ribose) Polymerase Inhibition in Patients with Breast Cancer and BRCA 1 and 2 Mutations


The poly-(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib, have recently been approved for use in patients with metastatic breast cancer (BC) and germline BRCA 1 or 2 mutations due to improved progression-free survival compared to chemotherapy. An increasing number of clinical trials are evaluating the role of PARP inhibitors (PARPi) in BC, alone and in combination with other therapies (including immunotherapy), as well as in earlier stages of the disease. This review describes the unique mechanism of action of these drugs and puts into clinical context the results of pivotal clinical trials. We also discuss the future development of PARPi in BC, their potential combination with other strategies, including chemotherapy and immune-checkpoint inhibitors, and the impact of these treatments in current genetic counselling.

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  1. 1.

    Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33.

  2. 2.

    Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee K-H, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753–63.

  3. 3.

    Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008;9:619–31.

  4. 4.

    Murai J, Huang S-YN, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13:433–43.

  5. 5.

    Andreopoulou E, Sparano JA. Chemotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer: an overview. Curr Breast Cancer Rep. 2013;5:42–50.

  6. 6.

    Le Du F, Perrin C, Brunot A, Crouzet L, De La Motte Rouge T, Lefeuvre-Plesse C, et al. Therapeutic innovations in breast cancer. Presse Méd. 2019;S0755498219301654.

  7. 7.

    Shao N, Shi Y, Yu L, Ye R, Shan Z, Zhang Z, et al. Prospect for application of PARP inhibitor in patients with HER2 negative breast cancer. Int J Biol Sci. 2019;15:962–72.

  8. 8.

    Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res. 2012;14:R110.

  9. 9.

    Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018;24:628.

  10. 10.

    Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, et al. A phase II study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO). Clin Cancer Res. 2019;25:2717–24.

  11. 11.

    Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AOH, Zander SAL, 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 USA. 2008;105:17079–84.

  12. 12.

    Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AOH, et al. Poly(ADP-Ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-Mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009;69:3850–5.

  13. 13.

    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.

  14. 14.

    Keung MYT, Wu Y, Vadgama JV. PARP inhibitors as a therapeutic agent for homologous recombination deficiency in breast cancers. J Clin Med. 2019;8:435.

  15. 15.

    Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235–44.

  16. 16.

    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;376:245–51.

  17. 17.

    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;12:852–61.

  18. 18.

    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;28:2512–9.

  19. 19.

    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.

  20. 20.

    Zimmer AS, Gillard M, Lipkowitz S, Lee J-M. Update on PARP inhibitors in breast cancer. Curr Treat Options Oncol. 2018;19:21.

  21. 21.

    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;114:723–30.

  22. 22.

    A study to assess the efficacy of rucaparib in metastatic breast cancer patients with a BRCAness genomic signature. [Internet]. [cited 2019 Jun 29].

  23. 23.

    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;7:620–9.

  24. 24.

    Litton JK, Scoggins M, Ramirez DL, Murthy RK, Whitman GJ, Hess KR, et al. A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. NPJ Breast Cancer. 2017;6(3):49.

  25. 25.

    Kohn EC, Lee J, Ivy SP. The HRD decision—which PARP inhibitor to use for whom and when. Clin Cancer Res. 2017;23:7155–7.

  26. 26.

    Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol. 2019.

  27. 27.

    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;14:882–92.

  28. 28.

    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;375:2154–64.

  29. 29.

    A feasibility study of niraparib for advanced, BRCA1-like, HER2-negative breast cancer patients. [Internet]. [cited 2019 Jun 29].

  30. 30.

    Puhalla S, Beumer JH, Pahuja S, Appleman LJ, Tawbi HA-H, Stoller RG, et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA +), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). J Clin Oncol. 2014;32:2570.

  31. 31.

    Robson ME, Tung N, Conte P, Im S-A, Senkus E, Xu B, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30:558–66.

  32. 32.

    Tryfonidis K, Bogaerts J, Martell RE, Sledge GW, Balmaña J, Audeh MW, et al. A phase III randomized trial of niraparib versus physician’s choice in previously treated, HER2-negative, germline-BRCA mutated breast cancer patients: intergroup study EORTC-1307-BCG and BIG5-13. J Clin Oncol. 2014;32:TPS659.

  33. 33.

    A phase III trial of niraparib versus physician’s choice in HER2 negative, germline BRCA mutation-positive breast cancer patients. [Internet]. [cited 2019 Jun 29].

  34. 34.

    Inc T. TESARO Announces Expanded Development Program for Niraparib Focused on the Treatment of Front-Line Metastatic Ovarian and Lung Cancers and Metastatic Breast Cancer [Internet]. 2017 [cited 2019 Jun 29].

  35. 35.

    Lee J-M, 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;23:1397–406.

  36. 36.

    Han HS, Diéras V, Robson M, Palácová M, Marcom PK, Jager A, et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Ann Oncol. 2018;29:154–61.

  37. 37.

    Diéras V, Han HS, Kaufman B, Wildieres H, Friedlander M, Ayoub J, et al. Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer: BROCADE3. Ann Oncol. 2019;30(suppl_5):v851–934.

  38. 38.

    Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig New Drugs. 2012;30:1493–500.

  39. 39.

    Dean E, Middleton MR, 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 tumours. Br J Cancer. 2012;106:468–74.

  40. 40.

    Diossy M, Reiniger L, Sztupinszki Z, Krzystanek M, Timms KM, Neff C, et al. Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors. Ann Oncol. 2018;29:1948–54.

  41. 41.

    Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neurooncol. 2015;122:409–17.

  42. 42.

    Wielgos ME, Zhang Z, Rajbhandari R, Cooper TS, Zeng L, Forero A, et al. Trastuzumab-resistant HER2 + breast cancer cells retain sensitivity to poly (ADP-Ribose) polymerase (PARP) inhibition. Mol Cancer Ther. 2018;17:921–30.

  43. 43.

    García-Parra J, Dalmases A, Morancho B, Arpí O, Menendez S, Sabbaghi M, et al. Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer. Eur J Cancer. 2014;50:2725–34.

  44. 44.

    Geenen JJJ, Linn SC, Beijnen JH, Schellens JHM. PARP inhibitors in the treatment of triple-negative breast cancer. Clin Pharmacokinet. 2018;57:427–37.

  45. 45.

    Do K, Doroshow JH, Kummar S. Wee1 kinase as a target for cancer therapy. Cell Cycle. 2013;12:3159–64.

  46. 46.

    Yap TA, Plummer R, Azad NS, Helleday T. The DNA damaging revolution: PARP inhibitors and beyond. Am Soc Clin Oncol Educ Book. 2019;39:185–95.

  47. 47.

    Lu H, Bai L, Zhou Y, Lu Y, Jiang Z, Shi J. Recent study of dual HDAC/PARP inhibitor for the treatment of tumor. Curr Top Med Chem. 2019;19(12):1041–50.

  48. 48.

    De P, Sun Y, Carlson JH, Friedman LS, Leyland-Jones BR, Dey N. Doubling down on the PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness. Neoplasia. 2014;16:43.

  49. 49.

    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;28:512–8.

  50. 50.

    Botty RE, Coussy F, Hatem R, Assayag F, Chateau-Joubert S, Servely J-L, et al. Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition. Oncotarget. 2018;9:29587–600.

  51. 51.

    Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 2016;17:2367–81.

  52. 52.

    Wang X, Shi Y, Huang D, Guan X. Emerging therapeutic modalities of PARP inhibitors in breast cancer. Cancer Treat Rev. 2018;68:62–8.

  53. 53.

    Jiao S, Xia W, Yamaguchi H, Wei Y, Chen M-K, Hsu J-M, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23:3711–20.

  54. 54.

    Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019.

  55. 55.

    Domchek SM, Postel-Vinay S, Im S-A, Park YH, Delord J-P, Italiano A, et al. Abstract PD5-04: An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Cancer Res. 2019;79:PD5–04–PD5–04.

  56. 56.

    Rugo HS, Olopade OI, DeMichele A, Yau C, van’t Veer LJ, van’t Buxton MB, et al. Adaptive randomization of veliparib–carboplatin treatment in breast cancer. N Engl J Med. 2016;375:23–34.

  57. 57.

    Loibl S, O’Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19:497–509.

  58. 58.

    Robson ME, Ruddy KJ, Im S-A, Senkus-Konefka E, Xu B, Domchek SM, et al. EORTC QLQ-C30 (QLQ-C30) symptoms in patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib vs chemotherapy treatment of physician’s choice (TPC) in OlympiAD. J Clin Oncol. 2018;36:1045.

  59. 59.

    Ettl J, Quek RGW, Lee K-H, Rugo HS, Hurvitz S, Gonçalves A, et al. Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol. 2018;29:1939–47.

  60. 60.

    McCrea C, Hettle R. Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer. J Clin Oncol. 2019;37:e12570.

  61. 61.

    Antolin AA, Ameratunga M, Banerji U, Clarke P, Workman P, Al-Lazikani B. The off-target kinase landscape of clinical PARP inhibitors. Pharmacol Toxicol. 2019.

  62. 62.

    Poggio F, Bruzzone M, Ceppi M, Conte B, Martel S, Maurer C, et al. Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis. ESMO Open. 2018;3:e000361.

  63. 63.

    Póti Á, Berta K, Xiao Y, Pipek O, Klus GT, Ried T, et al. Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts. Br J Cancer. 2018;119:1392.

  64. 64.

    Gyawali B. Low-value practices in oncology contributing to financial toxicity. Ecancermedicalscience. 2017;11:727.

  65. 65.

    Cherny NI, Dafni U, Bogaerts J, Latino NJ, Pentheroudakis G, Douillard J-Y, et al. ESMO-magnitude of clinical benefit scale version 1.1. Ann Oncol. 2017;28:2340–66.

  66. 66.

    Robson M, Ruddy KJ, Im S-A, Senkus-Konefka E, Xu B, Domchek SM, et al. 290POlympiAD: Health-related quality of life (HRQoL) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib monotherapy vs standard single-agent chemotherapy treatment of physician’s choice (TPC). Ann Oncol. 2017;28(suppl_5):v74–108.

  67. 67.

    Hurvitz SA, Quek RGW, Turner NC, Telli ML, Rugo HS, Mailliez A, et al. Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. Eur J Cancer. 2018;104:160–8.

  68. 68.

    Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 4)†. Ann Oncol. 2018;29:1634–57.

  69. 69.

    Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.

  70. 70.

    Savard M-F, Khan O, Hunt KK, Verma S. Redrawing the lines: the next generation of treatment in metastatic breast cancer. Am Soc Clin Oncol Educ Book. 2019;39:e8–21.

  71. 71.

    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

  72. 72.

    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265:2088–90.

  73. 73.

    Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863–71.

  74. 74.

    Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. 2016;27:v103–10.

  75. 75.

    Forbes C, Fayter D, de Kock S, Quek RG. A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer. Cancer Manag Res. 2019;11:2321–37.

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Correspondence to Miguel Martín.

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Conflict of interest

Yolanda Jerez has a consultant or advisory role at Novartis, Pfizer, Roche, and AstraZeneca and has received speaker honoraria from Roche, Novartis, and AstraZeneca and travel grants from Roche, Novartis, Pfizer, and Teva. Ivan Márquez-Rodas has a consultant or advisory role and travel grants from BMS, MSD, Novartis, Pierre Fabre, Roche, Regeneron, Sanofi, Amgen, Bioncotech, MERCK-serono, Incyte. Miguel Martín has received research grants from Roche, PUMA, and Novartis; consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; and speakers’ honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi Sankyo, and Pfizer. Sara López-Tarruella has a consultant or advisory role at Celgene, Novartis, Pierre Fabre, Pfizer, Roche, Eisai, and Lilly and an AZ travel grant from Celgene, Pfizer, Roche, and MSD. Inmaculada Aparicio and Manuel Alva declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Jerez, Y., Márquez-Rodas, I., Aparicio, I. et al. Poly (ADP-ribose) Polymerase Inhibition in Patients with Breast Cancer and BRCA 1 and 2 Mutations. Drugs 80, 131–146 (2020).

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