第一個針對BRCA突變卵巢癌的標靶治療：Olaparib

The First Targeted Therapy toward BRCA-mutated Ovarian Cancer: Olaparib

10.6880/TJON.201812_18(2).02

姜紹青(Shao-Chin Chiang)

乳癌易感基因 ； 卵巢癌 ； DNA受損反應路徑 ； BRCA (breast cancer susceptibility gene) ； ovarian cancer ； DNA damage response pathway (DDR) ； Olaparib

腫瘤護理雜誌

18卷2期（2018 / 12 / 01）

13 - 20

繁體中文

表皮卵巢癌是全世界女性第七名高的發生率。台灣女性癌症中的第九高。在2006至2013年間，雖然全球的重大研究中，沒有任何一個新藥在治療卵巢癌領域被核准。Olaparib在2014首度在美國食物藥品管理署被核准單一治療用於具有傷害性或懷疑的BRCA突變晚期且已經三或更多的化學治療；2017年再加上具有乳癌易感基因（breast cancer susceptibility gene,BRCA）突變的卵巢癌，對鉑類化療已經完全或部分反應後之維持療法。2018年6月5日olaparib在臺灣取得許可證。Olaparib是PARP酵素抑制劑的第一個上市藥品。PARP酵素在DNA受損反應路徑（DDR）特別是鹼基排除修護（BER）或單股斷片修護（SSBR）負責DNA受損修護的工作。臨床試驗（SOLO-2）中，證實在具有生殖細胞BRCA突變的卵巢癌、輸卵管癌、原發腹膜癌的病人，先前都接受過鉑化學治療，且最近一次對於鉑化學治療有萬全或部分反應者，Olaparib被證實可以延長無惡化存活期。主要副作用為血液學副作用，極少數（＜1%）病人在試驗中發生骨髓增生不良症候群與急性骨髓性白血病，所以接受本藥的病人，需要有全血球計數的基線值與定期檢測。

Epithelial ovarian cancer ranks top seven in female cancer incidence worldwide and top nine in Taiwan. From 2006 to 2013, there was not any antineoplastic agent approved for this disease. In 2014, US FDA approved the first targeted agent, Olaparib, for BRCA-mutated ovarian cancer after 3 or more prior chemotherapy. Then in 2017, Olaparib was approved for BRCA mutation maintenance after complete/partial response to platinum chemotherapy. Taiwan also gave her FDA approval to Olaparib in June, 2018. The mechanism of Olaparib is to inhibit poly(ADP-ribose) polymerase, which plays a vital role in the DNA damage repair. In the SOLO 2 trial, a phase III trial for ovarian, fallopian, and primary peritoneal cancer, patients with BRCA mutation maintenance therapy after complete/partial response to platinum chemotherapy responded to Olaparib with prolonged progression-free survival. The major adverse effects of Olaparib are mainly hematological. Very few (＜1%) patients in the clinical trial showed myelodysplastic syndrome or acute mylogenous leukemia after the start of therapy. Baseline and periodical complete blood counts need to be monitored.

1. fda.gov [webpage on the Internet]. FDA Grants Accelerated Approval to New Treatment for Advanced Ovarian Cancer. Available from: https://www.fda.gov/newsevents/newsroom/ pressannouncements/ucm533873.htm. Accessed December 3, 2018.
2. 2015年癌症登記年報 https://www.hpa.gov. tw/Pages/Detail.aspx?nodeid3269&pid=8084
3. 令癌莎仿單,臺灣食物藥品管理局西藥醫療器材、含藥化粧品許可證查詢網頁 https://www.fda.gov.tw/mlms/H0001D.aspx?- Type=Lic&LicId=52027445 Accessed Decem- ber 3, 2018. Lic&LicId
4. (2014).AstraZeneca UK limited. Lynpraza (olaparib) 50 mg hard capsule summary of product characteristics. 2014 Jan..
5. fda.gov [webpage on the Internet]. FDA Approves Olaparib Tablets for Maintenance Treatment in Ovarian Cancer. Available from: https://www.fda.gov/drugs/informationon- drugs/approveddrugs/ucm572143.htm. Accessed December 3, 2018.
6. fda.gov [webpage on the Internet]. FDA Approves Maintenance Treatment for Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancers. Available from: https:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm548948.htm. Accessed December 3, 2018.
7. Olaparib [Lynpaza] USFDA approved pack- age insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206162s011lbl.pdf Accessed December 3, 2018.
8. Alsop, K,Fereday, S,Meldrum, C(2012).BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Austra- lian Ovarian Cancer Study Group.J Clin Oncol,30(21),2654-2663.
9. Ame, JC,Spenlehauer, C,de Murcia, G.(2004).The PARP superfamily.Bioessays,26(8),882-893.
10. Audeh, MW,Carmichael, J,Penson, RT(2010).Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concepttrial.Lancet,376(9737),245-251.
11. Bryant, HE,Petermann, E,Schultz, N(2009).PARP is activated at stalled forks to mediate Mrel1-dependent replication restart and recombination.EMBO J,28(17),2601-2615.
12. Bryant, HE,Schultz, N,Thomas, HD(2005).Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature,434(7035),913-917.
13. De Bont, R,van Larebeke, N.(2004).Endogenous DNA damage in humans: A review of quantitative data.Mutagenesis,19(3),169-185.
14. Farmer, H,McCabe, N,Lord, CJ(2005).Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature,434(7035),917-921.
15. Ferraris, DV(2010).Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic.J Med Chem,53(12),4561-4584.
16. Fong, PC,Boss, DS,Yap, TA(2009).Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N Engl J Med,361(2),123-134.
17. Helleday, T.(2011).The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.Mol Oncol,5(4),387-393.
18. Hoeijmakers, JH(2009).DNA damage, aging, and cancer.N Engl J Med,361(15),1475-1485.
19. Hoeijmakers, JH(2001).Genome maintenance mechanisms for preventing cancer.Nature,411(6835),366-374.
20. Huertas, P.(2010).DNA resection in eukaryotes: deciding how to fix the break.Nat Struct Mol Biol,17(1),11-16.
21. IARC(2014).World Cancer Report 2014.Switzerland:World Health Organisation.
22. Jeggo, PA,Pearl, LH,Carr, AM(2016).DNA repair, genome stability and cancer: A historical perspective.Nat Rev Cancer,16(1),35-42.
23. Kaufman, B,Shapira-Frommer, R,Schmutzler, RK(2015).Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.J Clin Oncol,33,244-250.
24. Ledermann, J,Harter, P,Gourley, C(2012).Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med,366(15),1382-1392.
25. Lindahl, T.(1993).Instability and decay of the primary structure of DNA.Nature,362(6422),709-715.
26. Miki, Y,Swensen, J,Shattuck-Eidens, D(1994).A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Science,266(5182),66-71.
27. Milam, KM,Cleaver, JE(1984).Inhibitors of poly(adenosine diphosphate-ribose) synthesis: Effect on other metabolic processes.Science,223(4636),589-591.
28. Mirza, MR,Monk, BJ,Herrstedt, J(2016).Nirapa-rib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med,375(22),2154-2164.
29. Neale, MJ,Keeney, S.(2006).Clarifying the mechanics of DNA strand exchange in meiotic recombination.Nature,442(7099),153-158.
30. Pennington, KP,Walsh, T,Harrell, MI(2014).Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.Clin Cancer Res,20(3),764-775.
31. Rouleau, M,Patel, A,Hendzel, MJ,Kaufmann, SH,Poirier, GG.(2010).PARP inhibition: PARP1 and beyond.Nat Rev Cancer,10(4),293-301.
32. Schreiber, V,Dantzer, F,Ame, JC,de Murcia, G.(2006).Poly(ADP-ribose): novel functions for an old molecule.Nat Rev Mol Cell Biol,7(7),517-528.
33. Seidman, JD,Horkayne-Szakaly, I,Haiba, M,Boice, CR,Ronnett, BM(2004).The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin.Int J Gynecol Pathol,23(1),41-44.
34. Siegel, R,Naishadham, D,Jemal, A.(2012).Cancer sta- tistics, 2012.CA Cancer J Clin,62(1),10-29.
35. Swisher, EM,Lin, KK(2017).Rucapa-rib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an inter- national, multicentre, open-label, phase 2 trial.Lancet Oncol,18(1),75-87.
36. US Food and Drug Administartion.US Food and Drug Administartion. Center for Drug Evaluation and Research. Application number 206162Orig1s000: Medical reviews..
37. Wooster, R,Bignell, G,Lancaster, J(1995).Identification of the breast cancer susceptibility gene BRCA2.Nature,378(6559),789-792.