Olaparib

Olaparib
Clinical data
Trade names Lynparza
License data
Routes of
administration		 Oral
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.170.811 Edit this at Wikidata
Chemical and physical data
Formula C24H23FN4O3
Molar mass 435.08 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved targeted therapy for cancer, developed by scientists at the University of Cambridge, including Steve Jackson, KuDOS Pharmaceuticals, and later by AstraZeneca. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.[2]

In December 2014, olaparib was approved for use as a single agent by the EMA and the FDA.[3][4][5] The FDA approval is for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[4] In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer.

Mechanism of action

Olaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment.[6][7][8][9][10][11]

Clinical studies

Phase I clinical trials showed activity in advanced breast, ovarian and prostate cancers which were no longer responding to previous therapy, including a castration-resistant prostate cancer that responded for several years;[2] activity was seen particularly in ovarian cancer.[12]

In 2009, phase II clinical trials of olaparib were initiated in breast, ovarian and colorectal cancer.[13][14] Activity was seen in ovarian cancer, with 7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.[15] However, in December 2011, AstraZeneca announced that an interim analysis of another phase II study that looked at using olaparib to maintain response after success with platinum-based chemotherapy[16] indicated that a reported progression-free survival benefit was unlikely to translate into an overall survival benefit; olaparib would not progress into phase III development, and AstraZeneca took a charge of $285 million.[17] However, planned analysis of the subset who had BRCA mutations found a clear advantage with olaparib, which renewed interest.[18][19][20] Accordingly, two phase III trials were initiated in BRCA mutated ovarian cancer in 2013.[21][22][23][24]

Approvals and indications

In December 2014, the FDA[4][5] and the EMA[3] approved olaparib as monotherapy, at a recommended dose of 400 mg taken twice per day. The FDA approval is in germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[4][25][26] The EMA public assessment report, which utilized the same phase II trial data, made reference to both "high grade serous ovarian cancers" and to the use of olaparib "not later than 8 weeks after a course of platinum-based medicines, when the tumour was diminishing in size or had completely disappeared",[3] reflecting the phase II trial of olaparib as maintenance therapy in platinum-sensitive relapsed serous ovarian cancer.[27][28][29]

In breast cancer, olaparib is approved for gBRCAm HER2-negative metastatic breast cancer patients who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. If patients have hormone receptor positive cancer, they should have received endocrine therapy where appropriate.[30] This approval was based on the OlympiAD randomised phase III trial, which showed a progression-free survival benefit for patients treated with olaparib compared to conventional chemotherapy [31][32]

Side effects

Side effects include gastrointestinal effects such as nausea, vomiting, and loss of appetite; fatigue; muscle and joint pain; and low blood counts such as anemia, with occasional leukemia.[4] Somnolence was sometimes seen in clinical trials which used doses higher than the approved schedule.[2]

References

  1. ↑ "Olaparib, a PARP Inhibitor". Health and Life.
  2. 1 2 3 Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (July 2009). "Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers". The New England Journal of Medicine. 361 (2): 123–34. doi:10.1056/NEJMoa0900212. PMID 19553641.
  3. 1 2 3 "Summary" (PDF). ema.europa.eu.
  4. 1 2 3 4 5 Olaparib (Lynparza) package insert at FDA.gov
  5. 1 2 "Summary". fda.gov.
  6. ↑ "New cancer drug 'shows promise'". BBC News Health bbc.co.uk.
  7. ↑ "Olaparib for the treatment of ovarian cancer" (PDF). europa.eu.
  8. ↑ Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM (October 2008). "4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1". Journal of Medicinal Chemistry. 51 (20): 6581–91. doi:10.1021/jm8001263. PMID 18800822.
  9. ↑ Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J (November 2008). "High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs". Proceedings of the National Academy of Sciences of the United States of America. 105 (44): 17079–84. doi:10.1073/pnas.0806092105. PMC 2579381. PMID 18971340.
  10. ↑ Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR (May 2009). "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 Research. 69 (9): 3850–5. doi:10.1158/0008-5472.CAN-08-2388. PMID 19383921.
  11. ↑ Cambridge University (2014-12-24), PARP-inhibitors: A New Generation of Cancer Drugs, retrieved 2018-06-12
  12. ↑ http://www.ncri.org.uk/ncriconference/archive/2007/abstracts/pdf/LB57.pdf "A Phase I trial of AZD2281 (KU-0059436), a PARP inhibitor with single agent anticancer activity in patients with BRCA deficient tumours, particularly ovarian cancer"
  13. ↑ http://www.cancercompass.com/cancer-news/1,15869,00.htm "Phase II Trials Investigating Oral PARP Inhibitor, Olaparib, In BRCA-Deficient Advanced Breast And Ovarian Cancer" June 2009
  14. ↑ Clinical trial number NCT00912743 for "Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status" at ClinicalTrials.gov
  15. ↑ "Olaparib Looks Promising in Treatment of Non-BRCA Ovarian Cancer". 26 Aug 2011.
  16. ↑ Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U (April 2012). "Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer". The New England Journal of Medicine. 366 (15): 1382–92. doi:10.1056/nejmoa1105535. PMID 22452356.
  17. ↑ "AZ updates on olaparib and TC5214". 20 December 2011.
  18. ↑ "ODAC Votes Against Maintenance Olaparib in BRCA-Positive Ovarian Cancer". onclive.com.
  19. ↑ "Olaparib Shows Robust Progression-Free Survival Benefit in Patients With BRCA Mutations - The ASCO Post". www.ascopost.com.
  20. ↑ "FDA review red-flags AstraZeneca's case for ovarian cancer drug olaparib". FierceBiotech.
  21. ↑ "Update: AstraZeneca reverses $285 mln charge as cancer trial starts". Reuters UK.
  22. ↑ Moore KN, DiSilvestro P, Lowe ES, et al. SOLO1 and SOLO2: Randomized phase III trials of olaparib in patients (pts) with ovarian cancer and a BRCA1/2 mutation (BRCAm). 2014 ASCO Annual Meeting abstract TPS5616
  23. ↑ Clinical trial number Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy at ClinicalTrials.gov
  24. ↑ Clinical trial number NCT01874353 at ClinicalTrials.gov
  25. ↑ Wiggans AJ, Cass GK, Bryant A, Lawrie TA, Morrison J (May 2015). "Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer". The Cochrane Database of Systematic Reviews (5): CD007929. doi:10.1002/14651858.CD007929.pub3. PMID 25991068.
  26. ↑ "Olaparib clinical trial references & regimen". HemOnc.org.
  27. ↑ Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U (July 2014). "Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial". The Lancet. Oncology. 15 (8): 852–61. doi:10.1016/S1470-2045(14)70228-1. PMID 24882434.
  28. ↑ Ledermann J, Harter P, Gourley C (April 2015). "Correction to Lancet Oncol 2014; 15: 856. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial". The Lancet. Oncology. 16 (4): e158. doi:10.1016/S1470-2045(15)70153-1. PMID 25846095.
  29. ↑ Clinical trial number NCT00753545 for "Assessment of Efficacy of AZD2281 in Platinum Sensitive Relapsed Serous Ovarian Cancer" at ClinicalTrials.gov
  30. ↑ "Olaparib (Lynparza) package insert (January 2018)" (PDF). fda.gov.
  31. ↑ Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P (August 2017). "Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation". The New England Journal of Medicine. 377 (6): 523–533. doi:10.1056/NEJMoa1706450. PMID 28578601.
  32. ↑ Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves olaparib for germline BRCA-mutated metastatic breast cancer". www.fda.gov.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.