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Olaparib

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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
Legal status
  • Investigational
Routes Oral
Identifiers
CAS number  N
ATC code None
PubChem
ChemSpider  YesY
UNII  YesY
ChEMBL  YesY
Chemical data
Formula C24H23FN4O3 
Mol. mass 435.08 g/mol
 N   

Olaparib (AZD-2281, trade name Lynparza) is an experimental chemotherapeutic agent, developed by KuDOS Pharmaceuticals and later by AstraZeneca, that is currently undergoing clinical trials. It is an inhibitor of 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 includes many ovarian, breast and prostate cancers.

Early Phase I trials were promising, and olaparib underwent Phase II trials. However, in December 2011, AstraZeneca announced following interim analysis of a phase-II study which indicated that the previously reported progression free survival benefit was unlikely to translate into an overall survival benefit, that it would not progress into Phase III development for the maintenance treatment of serous ovarian cancer,[2] and took a charge of $285 million. The decision to discontinue development of the drug was reversed in 2013,[3] with AstraZeneca posting a new Phase III trial of Olaparib for patients with BRCA mutated ovarian cancer in April 2013.[4]

Mechanism of action

Olaparib acts as an inhibitor of the enzyme Poly ADP ribose polymerase (PARP) and is one of the first PARP inhibitors. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers 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 significant benefit in patients whose cancers are susceptible to this treatment.[5][6][7][8][9][10]

Trial results

Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging.[11] In one of these studies, it was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancers caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised.[12] One of the first patients to be given the treatment (who had castration-resistant prostate cancer) was as of July 2009 still in remission after two years.

In 2009 Phase II clinical trials examining the efficacy of Olaparib in treating breast, ovarian and colorectal cancer were initiated.[13][14] A phase II trial that included 63 cases of ovarian cancer concluded that olaparib is promising for women with ovarian cancer. [7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.][15]

Side effects

Olaparib is generally well tolerated, the side effects consist mainly of fatigue, somnolence, nausea, loss of appetite and thrombocytopenia.

References

  1. ^ "Olaparib, a PARP Inhibitor". Health and Life. 
  2. ^ "AZ updates on olaparib and TC5214". 20 December 2011. 
  3. ^ http://uk.reuters.com/article/2013/09/04/astrazeneca-cancer-idUKL6N0H00KN20130904
  4. ^ http://www.clinicaltrials.gov/ct2/show/NCT01844986
  5. ^ New cancer drug 'shows promise' BBC News 24 June 2009
  6. ^ Olaparib for the treatment of ovarian cancer.
  7. ^ Vasiliou S, Castaner R, Bolos J. Olaparib. Drugs of the Future. 2009; 34(2): 101.
  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.  
  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.  
  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.  
  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. ^ 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.  
  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. ^ http://clinicaltrials.gov/ct2/show/NCT00912743 Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status
  15. ^ "Olaparib Looks Promising in Treatment of Non-BRCA Ovarian Cancer". 26 Aug 2011. 
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