Olaparib

Olaparib (AZD-2281, MK-7339 trade name Lynparza) is an FDA-approved targeted therapy for cancer. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.[1]

Olaparib
Clinical data
Trade namesLynparza
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard100.170.811
Chemical and physical data
FormulaC24H23FN4O3
Molar mass435.08 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

In December 2014, olaparib was approved for use as a single agent by the EMA and the FDA.[2][3][4] The FDA approval is for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[3] In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer. Olaparib was developed and first dosed into patients by the UK-based biotechnology company, KuDOS Pharmaceuticals, that was founded by Stephen Jackson of Cambridge University, UK.[5][6][7] Since KuDOS was acquired by AstraZeneca in 2006, the drug has undergone clinical development by AstraZeneca and Merck & Co.[8]

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.[9][10]

Approvals and indications

In December 2014, the FDA[3][4] and the EMA[2] approved olaparib as monotherapy. The FDA approval is in germline BRCA mutated (gBRCAm) advanced ovarian cancer[11] that has received three or more prior lines of chemotherapy.[3][12] 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".[2]

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.[13] 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 [14][15]

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.[3] Somnolence was sometimes seen in clinical trials which used doses higher than the approved schedule.[1]

References
  1. 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.
  2. "Summary" (PDF). ema.europa.eu.
  3. Olaparib (Lynparza) package insert at FDA.gov
  4. "Summary". fda.gov.
  5. "Coming ever closer – first PARP inhibitor licensed in Europe" (science blog). Cancer Research UK. 24 October 2014.
  6. "KuDOS Pharmaceuticals: First Patient Treated with New Anti-cancer Agent" (press release). Institute of Cancer Research. 25 July 2005.
  7. "Olaparib: realising the promise of synthetic lethality". Cancer Research UK. 16 July 2015.
  8. "National Cancer Institute - Olaparib after Initial Treatment Delays Ovarian Cancer Progression".
  9. "Olaparib for the treatment of ovarian cancer" (PDF). europa.eu.
  10. 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.
  11. Article, MesoWatch. "Ovarian Cancer Patients Can Now Access Tumor Blocking Drug Olaparib at Beginning of the Treatment". www.mesowatch.com.
  12. 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. PMC 6457589. PMID 25991068.
  13. "Olaparib (Lynparza) package insert (January 2018)" (PDF). fda.gov.
  14. 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.
  15. Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves olaparib for germline BRCA-mutated metastatic breast cancer". www.fda.gov.
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