We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

A new targeted treatment for patients with a germline BRCA mutation: olaparib in pancreatic cancer

    Helena Verdaguer

    Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, 08035, Spain

    ,
    Daniel Acosta

    Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, 08035, Spain

    &
    Teresa Macarulla

    *Author for correspondence:

    E-mail Address: tmacarulla@vhio.net

    Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, 08035, Spain

    Published Online:https://doi.org/10.2217/fon-2020-0334

    Pancreatic cancer has a poor prognosis. Focused efforts in the development of novel treatments of this disease have led to the approval of new combinations. Improvements in knowledge of the biology of these tumors have been made, and it is now widely accepted that a proportion of patients have potentially targetable altered genes. One such gene is BRCA, which confers sensibility to PARP inhibitors. Olaparib, an oral PARP inhibitor, initially demonstrated activity in Phase II clinical trials including germline BRCA-mutated patients. This was confirmed in a Phase III clinical trial in pancreatic cancer patients with a germline BRCA mutation. After the results of this study, new scenarios have been evoked. We review the development of olaparib in pancreatic cancer.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
    • 2. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann. Oncol. 25(8), 1650–1656 (2014).
    • 3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74(11), 2913–2921 (2014).
    • 4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
    • 5. Salvia R, Fernández-Del Castillo C, Bassi C et al. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann. Surg. 239(5), 678 (2004).
    • 6. National Cancer Institute. Cancer stat facts: cancer of the pancreas. Surveillance: Epidemiology, and End Results Program. (2017). https://seer.cancer.gov/statfacts/html/pancreas.html
    • 7. Von Hoff DD, Ervin T, Arena FP et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369(18), 1691–1703 (2013). • Phase III clinical trial that demonstrates a new regimen for first-line treatment of metastatic pancreatic cancer.
    • 8. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364(19), 1817–1825 (2011). • Phase III clinical trial that demonstrates the efficacy of FOLFIRINOX in the treatment of first-line metastatic pancreatic cancer.
    • 9. Wang-Gillam A, Li C-P, Bodoky G et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, Phase III trial. Lancet 387(10018), 545–557 (2016).
    • 10. Bailey P, Chang DK, Nones K et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531(7592), 47 (2016).
    • 11. Waddell N, Pajic M, Patch AM et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540), 495–501 (2015).
    • 12. Alexandrov LB, Nik-Zainal S, Wedge DC et al. Signatures of mutational processes in human cancer. Nature 500(7463), 415 (2013).
    • 13. Consortium BCL. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91(15), 1310–1316 (1999).
    • 14. Thompson D, Easton DF. Cancer incidence in BRCA1 mutation carriers. J. Natl Cancer Inst. 94(18), 1358–1365 (2002).
    • 15. Holter S, Borgida A, Dodd A et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J. Clin. Oncol. 33(28), 3124–3129 (2015). • Prevalence of germline BRCA mutations in pancreatic cancer.
    • 16. Golan T, Kindler HL, Park JO et al. Geographic and ethnic heterogeneity in the BRCA1/2 pre-screening population for the randomized Phase III POLO study of olaparib maintenance in metastatic pancreatic cancer (mPC). J. Clin. Oncol. 36(Suppl. 15), 4115 (2018).
    • 17. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).
    • 18. Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16(2), 81–104 (2019).
    • 19. Golan T, Kanji ZS, Epelbaum R et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br. J. Cancer 111(6), 1132–1138 (2014). • Clinical characteristics of BRCA-mutated patients.
    • 20. Pishvaian MJ, Blais EM, Brody JR et al. Outcomes in patients with pancreatic adenocarcinoma with genetic mutations in DNA damage response pathways: results from the Know Your Tumor Program. JCO Precision Oncol. 3, 1–10 (2019).
    • 21. Dobzhansky TJG. Genetics of natural populations. XIII. Recombination and variability in populations of Drosophila pseudoobscura. 31(3), 269 (1946).
    • 22. Lord CJ, Ashworth A. PARP inhibitors: the first synthetic lethal targeted therapy. Science (New York, NY) 355(6330), 1152 (2017).
    • 23. Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 434(7035), 913 (2005).
    • 24. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035), 917 (2005).
    • 25. Yelamos J, Farres J, Llacuna L, Ampurdanes C, Martin-Caballero J. PARP-1 and PARP-2: new players in tumour development. 1(3), 328 (2011).
    • 26. Murai J, Shar-Yin NH, Das BB et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72(21), 5588–5599 (2012).
    • 27. Lord CJ, Ashworth AJS. PARP inhibitors: the first synthetic lethal targeted therapy. 355(6330), 1152 (2017).
    • 28. Ceccaldi R, Rondinelli B, D'Andrea ADJTICB. Repair pathway choices and consequences at the double-strand break. 26(1), 52–64 (2016).
    • 29. Fong PC, Boss DS, Yap TA et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361(2), 123–134 (2009).
    • 30. Menear KA, Adcock C, Boulter R et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one: a novel bioavailable inhibitor of poly (ADP-ribose) polymerase-1. J. Med. Chem. 51(20), 6581–6591 (2008).
    • 31. Rolfo C, Swaisland H, Leunen K et al. Effect of food on the pharmacokinetics of olaparib after oral dosing of the capsule formulation in patients with advanced solid tumors. Adv. Ther. 32(6), 510–522 (2015).
    • 32. Evers B, Drost R, Schut E et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14(12), 3916–3925 (2008).
    • 33. Rottenberg S, Jaspers JE, Kersbergen A 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. 105(44), 17079–17084 (2008).
    • 34. Fong PC, Boss DS, Yap TA et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361(2), 123–134 (2009).
    • 35. Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33(3), 244–250 (2014). •• First study that shows activity of olaparib in pancreatic cancer.
    • 36. Golan T, Hammel P, Reni M et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381(4), 317 (2019). •• Phase III clinical trial that demonstrates efficacy of olaparib manteinance in metastatic pancreatic cancer.
    • 37. Heo Y-A, Dhillon S. Olaparib tablet: a review in ovarian cancer maintenance therapy. Target. Oncol. 13(6), 801–808 (2018).
    • 38. Teresa Macarulla HLK, Pascal Hammel, Michele Reni et al. Early progression in patients with metastatic pancreatic cancer anda germline BRCA mutation: Phase III Polo trial of olaparib versus placebo. J. Clin. Oncol. 38(Suppl. 4), 750 (2020).
    • 39. Michele Reni HLK, Pascal Hammel, Eric van Cutsem et al. Adverse events with maintenance olaparib in patients with a germline BRCA mutation and metastatic pancreatic cancer: Phase III POLO trial. J. Clin. Oncol. 38(Suppl. 4), 686 (2020).
    • 40. Shroff RT, Hendifar A, Mcwilliams RR et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precision Oncol. 2, 1–15 (2018).
    • 41. Binder KaR, Mick R, O'Hara M et al. A Phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2, PALB2. Presented at: Cancer Research. GA, USA (2019).
    • 42. O'reilly EM, Lee JW, Lowery MA et al. Phase I trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer 124(7), 1374–1382 (2018).
    • 43. Golan T, Varadhachary GR, Sela T et al. Phase II study of olaparib for BRCAness phenotype in pancreatic cancer. J. Clin. Oncol. 36(Suppl. 4), 297 (2018).
    • 44. Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat. Rev. Clin. Oncol. 17, 1–16 (2019).
    • 45. Kristeleit R, Shapiro GI, Burris HA et al. A Phase I–II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin. Cancer Res. 23(15), 4095–4106 (2017).
    • 46. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, Phase II trial. Lancet Oncol. 18(1), 75–87 (2017).
    • 47. O'reilly EM, Lee JW, Zalupski M et al. Randomized, multicenter, Phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation. J. Clin. Oncol. 38(13), 1378–1388 (2020).