Prospects of PARP Inhibitors in Treatment of BRCA-Mutated Pancreatic Cancer: a Literature Review

Pancreatic adenocarcinoma has a  5-year overall survival rate of 9 %, with an outlook of becoming the second leading cause of cancer mortality in the USA by 2030. Familial pancreatic cancer and genetic predisposition syndromes have attracted more interest in the perspective of targeted therapy. Various authors estimate genetic causes to account for 10–15 % of pancreatic cancers. The BRCA gene mutations comprise the today’s most relevant genetic predisposition syndrome. The frequency of BRCA1/2 and PALB2 germinal mutations in patients with pancreatic adenocarcinoma constitutes about 5–9 %. Over recent years, PARP inhibitors (PARPi) have composed a new targeted therapy class with a significant effect in breast and ovarian cancers. With the mechanism of action of the PARP inhibitor and platinum drugs targeting different DNA repair pathways, their combination therapy has been suggested as promising. We report studies of a combination treatment with veliparib, gemcitabine and cisplatin in germinal BRCA1/2-mutation patients with advanced wild-type pancreatic adenocarcinoma (WT). Recent advances have identified patients with germinal and somatic mutations in the BRCA1/2 and other genes. HRD-targeted therapy, including platinum and PARP inhibitor drugs, can significantly improve survival. 

1. Rahib L., Smith B.D., Aizenberg R., Rosenzweig A.B., Fleshman J.M., Matrisian L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21. DOI: 10.1158/0008-5472. CAN-14-0155

2. Cancer Stat Facts: Pancreatic Cancer. National Cancer Institute: SEER [cited 2022 Feb 28]. Available from: https://seer.cancer.gov/statfacts/html/pancreas.html.

3. Ansari D., Friess H., Bauden M., Samnegård J., Andersson R. Pancreatic cancer: disease dynamics, tumor biology and the role of the microenvironment. Oncotarget. 2018;9(5):6644–51. DOI: 10.18632/oncotarget.24019

4. Azar I., Virk G., Esfandiarifard S., Wazir A., Mehdi S. Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: a nationwide study. J Gastrointest Oncol. 2019;10(4):703–11. DOI: 10.21037/jgo.2018.07.08

5. Sultanbaev A., Minniakhmetov I., Menshikov K., Sultanbaeva N., Nasretdinov A., Musin S. Identification of gene mutations in patients with breast cancer in a region located in the southeast of the European part of Russia. Ann Oncol. 2020;31(6):S1241–54. DOI: 10.1016/annonc/annonc351

6. Ben-David U., Beroukhim R., Golub T.R. Genomic evolution of cancer models: perils and opportunities. Nat Rev Cancer. 2019;19(2):97–109. DOI: 10.1038/s41568-018-0095-3

7. Birrer N., Chinchilla C., Del Carmen M., Dizon D.S. Is hormone replacement therapy safe in women with a BRCA mutation?: a systematic review of the contemporary literature. Am J Clin Oncol. 2018;41(3):313–5. DOI: 10.1097/COC.0000000000000269

8. Bartsch D.K., Matthäi E., Mintziras I., Bauer C., Figiel J., Sina-Boemers M., et al. The German national case collection for familial pancreatic carcinoma (FaPaCa)—knowledge gained in 20 years. Dtsch Arztebl Int. 2021;118(Forthcoming):163–8. DOI: 10.3238/arztebl.m2021.0004

9. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., Tavtigian S., et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71. DOI: 10.1126/science.7545954

10. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789–92. DOI: 10.1038/378789a0

11. Choi M., Kipps T., Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15(8):1781–91. DOI: 10.1158/1535-7163.MCT-15-0945

12. Chartron E., Theillet C., Guiu S., Jacot W. Targeting homologous repair deficiency in breast and ovarian cancers: biological pathways, preclinical and clinical data. Crit Rev Oncol Hematol. 2019;133:58–73. DOI: 10.1016/j.critrevonc.2018.10.012

13. Lowery M.A., Wong W., Jordan E.J., Lee J.W., Kemel Y., Vijai J., et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst. 2018;110(10):1067–74. DOI: 10.1093/jnci/djy024

14. Elta G.H., Enestvedt B.K., Sauer B.G., Lennon A.M. ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018;113(4):464–79. DOI: 10.1038/ajg.2018.14

15. Sekine M., Nishino K., Enomoto T. Differences in ovarian and other cancers risks by population and BRCA mutation location. Genes (Basel). 2021;12(7):1050. DOI: 10.3390/genes12071050

16. European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67(5):789–804. DOI: 10.1136/gutjnl-2018-316027

17. Faraoni I., Graziani G. Role of BRCA mutations in cancer treatment with Poly (ADP-ribose) polymerase (PARP) inhibitors. Cancers (Basel). 2018;10(12):487. DOI: 10.3390/cancers10120487

18. Hu C., Hart S.N., Polley E.C., Gnanaolivu R., Shimelis H., Lee K.Y., et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401–9. DOI: 10.1001/jama.2018.6228

19. Hu C., Hart S.N., Bamlet W.R., Moore R.M., Nandakumar K., Eckloff B.W., et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. Cancer Epidemiol Biomarkers Prev. 2016;25(1):207–11. DOI: 10.1158/1055-9965.EPI-15-0455

20. Salo-Mullen E.E., O’Reilly E.M., Kelsen D.P., Ashraf A.M., Lowery M.A., Yu K.H., et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer. 2015;121(24):4382–8. DOI: 10.1002/cncr.29664

21. Shindo K., Yu J., Suenaga M., Fesharakizadeh S., Cho C., MacgregorDas A., et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35(30):3382–90. DOI: 10.1200/JCO.2017.72.3502

22. Murphy K.M., Brune K.A., Griffin C., Sollenberger J.E., Petersen G.M., Bansal R., et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17 %. Cancer Res. 2002;62(13):3789–93. PMID: 12097290

23. George A., Kaye S., Banerjee S. Delivering widespread BRCA testing and PARP inhibition to pa tients with ovarian cancer. Nat Rev Clin Oncol. 2017;14(5):284–96. DOI: 10.1038/nrclinonc.2016.191

24. Golan T., Hammel P., Reni M., Van Cutsem E., Macarulla T., Hall M.J., et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–27. DOI: 10.1056/NEJMoa1903387

25. Sultanbaev A., Sultanbaeva N., Nasretdinov A., Menshikov K., Minniakhmetov I., Musin S., et al. Organization of screening for prostate cancer in carriers of germinal mutations in the BRCA1/2 genes. Eur Urol Open Sci. 2020;21(Suppl. 2):S59. DOI: 10.1016/S2666-1683(20)36064-X

26. Gröschel S., Hübschmann D., Raimondi F., Horak P., Warsow G., Fröhlich M., et al. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. Nat Commun. 2019;10(1):1635. DOI: 10.1038/s41467-019-09633-9

27. Gorodetska I., Kozeretska I., Dubrovska A. BRCA genes: the role in genome stability, cancer stemness and therapy resistance. J Cancer. 2019;10(9):2109–27. DOI: 10.7150/jca.30410

28. Godet I., Gilkes D.M. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther. 2017;4(1):10.15761/ICST.1000228. DOI: 10.15761/ICST.1000228

29. Roberts N.J., Jiao Y., Yu J., Kopelovich L., Petersen G.M., Bondy M.L., et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2(1):41–6. DOI: 10.1158/2159-8290.CD-11-0194

30. Sultanbaev A., Nasretdinov A., Sultanbaeva N., Menshikov K., Musin S., Izmailov A., et al. Hereditary prostate cancer screening. Eur Urol Open Sci. 2020;21(Suppl. 3):S155. DOI: 10.1016/S2666-1683(20)36212-1

31. van Os N.J., Roeleveld N., Weemaes C.M., Jongmans M.C., Janssens G.O., Taylor A.M., et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet. 2016;90(2):105–17. DOI: 10.1111/cge.12710

32. Zhen D.B., Rabe K.G., Gallinger S., Syngal S., Schwartz A.G., Goggins M.G., et al. BRCA1, BRCA2, PALB2, and CDKN2A muta tions in familial pancreatic cancer: a PACGENE study. Genet Med. 2014;17(7):569–77. DOI: 10.1038/gim.2014.153

33. Matsubayashi H., Takaori K., Morizane C., Kiyozumi Y. Familial pancreatic cancer and surveillance of high-risk individuals. Gut Liver. 2019;13(5):498–505. DOI: 10.5009/gnl18449

34. Konings I.C.A.W., Harinck F., Poley J-W., Aalfs C.M., van Rens A., Krak N.C., et al. Prevalence and progression of pancreatic cystic precursor lesions differ between groups at high risk of developing pancreatic cancer. Pancreas. 2017;46(1):28–34. DOI: 10.1097/MPA.0000000000000725

35. Chaffee K.G., Oberg A.L., McWilliams R.R., Majithia N., Allen B.A., Kidd J., et al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet Med. 2018;20(1):119–27. DOI: 10.1038/gim.2017.85

36. Borecka M., Zemankova P., Vocka M., Soucek P., Soukupova J., Kleiblova P., et al. Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer Genet. 2016;209(5):199–204. DOI: 10.1016/j.cancergen.2016.03.003

37. Wong W., Raufi A.G., Safyan R.A., Bates S.E., Manji G.A. BRCA Muta - tions in pancreas cancer: spectrum, current management, challenges and future prospects. Cancer Manag Res. 2020:12 2731–42. DOI: 10.2147/CMAR.S211151

38. Masamune A., Kikuta K., Hamada S., Nakano E., Kume K., Inui A., et al. Nationwide survey of hereditary pancreatitis in Japan. J Gastroen - terol. 2018;53(1):152–60. DOI: 10.1007/s00535-017-1388-0

39. Rebours V., Boutron-Ruault M.C., Schnee M., Férec C., Maire F., Hammel P., et al. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroen - terol. 2008;103(1):111–9. DOI: 10.1111/j.1572-0241.2007.01597.x

40. Shelton C.A., Umapathy C., Stello K., Yadav D., Whitcomb D.C. Hereditary pancreatitis in the United States: survival and rates of pan - creatic cancer. Am J Gastroenterol. 2018;113(9):1376. DOI: 10.1038/s41395-018-0194-5

41. Keihanian T., Barkin J.A., Souto E.O. Early detection of pancreatic cancer: risk factors and the current state of screening modalities. Gas - troenterol Hepatol (NY). 2021;17(6):254–62. PMID: 34776799

42. Syngal S., Brand R.E., Church J.M., Giardiello F.M., Hampel H.L., Burt R.W., et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223–62. DOI: 10.1038/ajg.2014.435

43. Tattersall A., Ryan N., Wiggans A.J., Rogozińska E., Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2022;2(2):CD007929. DOI: 10.1002/14651858.CD007929.pub4

44. Tutt A., Robson M., Garber J.E., Domchek S.M., Audeh M.W., Weitzel J.N., 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(9737):235–44. DOI: 10.1016/S0140-6736(10)60892-6

45. Lowery M.A., Lee A, Tobias E., Sung P., Bhanot U., Shakya R., et al. Evaluation of PARP inhibition as a platinum sparing strategy in Brca2-deficient pancreatic tumors. J Clin Oncol. 2014;32:e15237. DOI: 10.1200/jco.2014.32.15_suppl.e15237

46. McCabe N., Lord C.J., Tutt A.N., Martin N.M., Smith G.C., Ashworth A. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the in - hibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol Ther. 2005;4(9):934–6. DOI: 10.4161/cbt.4.9.2141

47. Lowery M.A., Kelsen D.P., Stadler Z.K., Yu K.H., Janjigian Y.Y., Ludwig E., et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implica - tions, and future directions. Oncologist. 2011;16(10):1397–402. DOI: 10.1634/theoncologist.2011-0185

48. Kaufman B., Shapira-Frommer R., Schmutzler R.K., Audeh M.W., Friedlander M., Balmaña J., et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50. DOI: 10. 1200/JCO.2014.56.2728

49. Lowery M.A., Kelsen D.P., Capanu M., Smith S.C., Lee J.W., Stadler Z.K., et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2017;89:19–26. DOI: 10.1016/j.ejca.2017.11.004

50. Kunzmann V., Algül N., Goekkurt E., Siegler G.M., Martens U.M., Waldschmidt D., et al. 671OConversion rate in locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/gemcitabine- or FOLFIRINOX-based induction chemotherapy (NEOLAP): Final results of a multicenter randomised phase II AIO trial. Ann Oncol. 2019;30(5):247. DOI: 10.1093/annonc/mdz247

51. Dahan L., Williet N., Le Malicot K., Phelip J.M., Desrame J., Bouché O., et al. Randomized phase II trial evaluating two sequential treatments in first line of metastatic pancreatic cancer: results of the PANOPTIMOXPRODIGE 35 Trial. J Clin Oncol. 2021;39(29):3242–50. DOI: 10.1200/JCO.20.03329

52. Golan T., Hammel P., Reni M., Cutsem E.V., Macarulla T., Hall M.J., et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317–27. DOI: 10.1056/NEJMoa1903387

53. O’Reilly E.M., Lee J.W., Lowery M.A., Capanu M., Stadler Z.K., Moore M.J., et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018;124(7):1374– 82. DOI: 10.1002/cncr.31218

54. O’Reilly E.M., Lee J.W., Zalupski M., Capanu M., Park J., Golan T., et al. Randomized, multicenter, phase ii trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adeno - carcinoma and a germline BRCA/PALB2 mutation. J Clin Oncol. 2020;38(13):1378–88. DOI: 10.1200/JCO.19.02931

55. Murai J., Zhang Y., Morris J., Ji J., Takeda S., Doroshow J.H., et al. Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J Pharmacol Exp Ther. 2014;349(3):408–16. DOI: 10.1124/jpet.113.210146

56. Yap T.A., Plummer R., Azad N.S., Helleday T. The DNA damaging revolution: PARP inhibitors and beyond. Am Soc Clin Oncol Edu. 2019;39:185–95. DOI: 10.1200/EDBK_238473

57. McCann K.E. Advances in the use of PARP inhibitors for RCA1/2associated breast cancer: talazoparib. Future Oncol. 2019;15(15):1707–15. DOI: 10.2217/fon-2018-0751

58. Pennington K.P., Walsh T., Harrell M.I., Lee M.K., Pennil C.C., Rendi M.H., 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. DOI: 10.1158/1078-0432.CCR-13-2287

59. Golmard L., Castéra L., Krieger S., Moncoutier V., Abidallah K., Tenreiro H., et al. Contribution of germline deleterious variants in the RAD51 paralogs to breast and ovarian cancers. Eur J Hum Genet. 2017;25(12):1345–53. DOI: 10.1038/s41431-017-0021-2

60. Villarroel M.C., Rajeshkumar N.V., Garrido-Laguna I., De Jesus-Acosta A., Jones S., Maitra A., et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011;10(1):3–8. DOI: 10.1158/1535-7163.MCT-10-0893

61. Chan D., Clarke S., Gill A.J., Chantrill L., Samra J., Li B.T., et al. Patho - genic PALB2 mutation in metastatic pancreatic adenocarcinoma and neuroendocrine tumour: a case report. Mol Clin Oncol. 2015;3(4):817– 9. DOI: 10.3892/mco.2015.533

62. Shroff R.T., Hendifar A., McWilliams R.R., Geva R., Epelbaum R., Rolfe L., et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis Oncol. 2018;2018:PO.17.00316. DOI: 10.1200/PO.17.00316

63. Lowery M.A., Jordan E.J., Basturk O., Ptashkin R.N., Zehir A., Berger M.F., et al. Real-time genomic profiling of pancreatic ductal adenocar - cinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res. 2017;23 (20):6094–100. DOI: 10.1158/1078-0432.CCR-17-0899

64. Mirza M.R., Monk B.J., Herrstedt J., Sc D.M., Oza A.M., Mahner S., et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64. DOI: 10.1056/NEJMoa1611310

65. Swisher E.M., Lin K.K., Oza A.M., Scott C.L., 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. DOI: 10.1016/S1470-2045(16)30559-9

66. Clarke N., Wiechno P., Alekseev B., Sala N., Jones R., Kocak I., et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(7):975–86. DOI: 10.1016/S1470-2045(18)30365-6

67. Hussain M., Mateo J., Fizazi K., Saad F., Shore N.D., Sandhu S., et al. LBA12_PR — PROfound: Phase III study of olaparib versus enzaluta - mide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene altera - tions. Ann Oncol. 2019;30(suppl.5):v881–2. DOI: 10.1093/annonc/mdz394.039