A new targeted treatment for patients with a germline BRCA mutation: olaparib in pancreatic cancer
Abstract
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. . 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. . European cancer mortality predictions for the year 2014. Ann. Oncol. 25(8), 1650–1656 (2014).
- 3. . 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. . Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
- 5. 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. 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. 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. 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. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531(7592), 47 (2016).
- 11. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540), 495–501 (2015).
- 12. 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. . Cancer incidence in BRCA1 mutation carriers. J. Natl Cancer Inst. 94(18), 1358–1365 (2002).
- 15. 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. 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. . Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).
- 18. . State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16(2), 81–104 (2019).
- 19. 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. 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. . Genetics of natural populations. XIII. Recombination and variability in populations of Drosophila pseudoobscura. 31(3), 269 (1946).
- 22. . PARP inhibitors: the first synthetic lethal targeted therapy. Science (New York, NY) 355(6330), 1152 (2017).
- 23. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 434(7035), 913 (2005).
- 24. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035), 917 (2005).
- 25. . PARP-1 and PARP-2: new players in tumour development. 1(3), 328 (2011).
- 26. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72(21), 5588–5599 (2012).
- 27. . PARP inhibitors: the first synthetic lethal targeted therapy. 355(6330), 1152 (2017).
- 28. . Repair pathway choices and consequences at the double-strand break. 26(1), 52–64 (2016).
- 29. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361(2), 123–134 (2009).
- 30. 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. 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. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14(12), 3916–3925 (2008).
- 33. 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. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361(2), 123–134 (2009).
- 35. 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. 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. . Olaparib tablet: a review in ovarian cancer maintenance therapy. Target. Oncol. 13(6), 801–808 (2018).
- 38. 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. 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. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precision Oncol. 2, 1–15 (2018).
- 41. 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. 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. Phase II study of olaparib for BRCAness phenotype in pancreatic cancer. J. Clin. Oncol. 36(Suppl. 4), 297 (2018).
- 44. . From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat. Rev. Clin. Oncol. 17, 1–16 (2019).
- 45. 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. 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. 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).