Olaparib

Olaparib
Systematic (IUPAC) name
4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one
Clinical data
Trade names Lynparza
Routes of
administration		 Oral
Legal status
Legal status
Identifiers
CAS Number 763113-22-0 N
ATC code L01XX46 (WHO)
PubChem CID 23725625
IUPHAR/BPS 7519
ChemSpider 23343272 YesY
UNII WOH1JD9AR8 YesY
ChEBI CHEBI:83766 N
ChEMBL CHEMBL521686 YesY
Chemical data
Formula C24H23FN4O3
Molar mass 435.08 g/mol
 NYesY (what is this?)  (verify)

Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved targeted therapy for cancer, developed by 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 in for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[4]

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]

Clinical activity

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.[11]

In 2009, phase II clinical trials of olaparib were initiated in breast, ovarian and colorectal cancer.[12][13] 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.[14] 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[15] 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.[16] However, planned analysis of the subset who had BRCA mutations found a clear advantage with olaparib, which renewed interest.[17][18][19] Accordingly, two phase III trials were initiated in BRCA mutated ovarian cancer in 2013.[20][21][22][23]

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][24][25] 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.[26][27][28]

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, et al. (July 2009). "Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers". N. Engl. J. Med. 361 (2): 123–34. doi:10.1056/NEJMoa0900212. PMID 19553641.
  3. 1 2 3 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003726/WC500180153.pdf
  4. 1 2 3 4 5 Olaparib (Lynparza) package insert at FDA.gov
  5. 1 2 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm
  6. ↑ "New cancer drug 'shows promise'". BBC News Health bbc.co.uk.
  7. ↑ Olaparib for the treatment of ovarian cancer.
  8. ↑ Menear KA, Adcock C, Boulter R, et al. (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, et al. (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, et al. (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. ↑ 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"
  12. ↑ 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
  13. ↑ http://clinicaltrials.gov/ct2/show/NCT00912743 Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status
  14. ↑ "Olaparib Looks Promising in Treatment of Non-BRCA Ovarian Cancer". 26 Aug 2011.
  15. ↑ http://www.nejm.org/doi/pdf/10.1056/NEJMoa1105535
  16. ↑ "AZ updates on olaparib and TC5214". 20 December 2011.
  17. ↑ http://www.onclive.com/web-exclusives/ODAC-Votes-Against-Maintenance-Olaparib-in-BRCA-Positive-Ovarian-Cancer#sthash.oj2bxdZC.dpuf
  18. ↑ http://www.ascopost.com/issues/september-1,-2013/olaparib-shows-robust-progression-free-survival-benefit-in-patients-with-brca-mutations.aspx
  19. ↑ "FDA review red-flags AstraZeneca's case for ovarian cancer drug olaparib". FierceBiotech.
  20. ↑ "Update: AstraZeneca reverses $285 mln charge as cancer trial starts". Reuters UK.
  21. ↑ 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
  22. ↑ "Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy. - Full Text View - ClinicalTrials.gov". clinicaltrials.gov.
  23. ↑ "Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. ClinicalTrials.gov". clinicaltrials.gov.
  24. ↑ Wiggans, Alison J; Cass, Gemma KS; Bryant, Andrew; et al. (2015). "Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer". doi:10.1002/14651858.CD007929.pub3.
  25. ↑ Olaparib clinical trial references & regimen "Ovarian cancer" Check |url= value (help). hemonc.org.
  26. ↑ Ledermann J, Harter P, Gourley C, et al. (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". Lancet Oncol. 15 (8): 852–61. doi:10.1016/S1470-2045(14)70228-1. PMID 24882434.
  27. ↑ Ledermann J, Harter P, Gourley C (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". Lancet Oncol. 16 (4): e158. doi:10.1016/S1470-2045(15)70153-1. PMID 25846095.
  28. ↑ https://clinicaltrials.gov/show/NCT00753545
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