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  Olaparib (AZD-2281)

Olaparib (AZD-2281) is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Olaparib (AZD-2281) is a chemotherapeutic agent developed by KuDOS Pharmaceuticals and later by Astra Zeneca. It is an inhibitor of PARP, an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers. Early (Phase I) trials have been promising, and it is now in Phase II trials, but is not clinically approved.

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.

Trial results: Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging. 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. One of the first patients to be given the treatment is still in remission after two years. Phase II clinical trials are ongoing in breast, ovarian and colorectal cancer. (Source: http://en.wikipedia.org/wiki/Olaparib.)

Current developer:   KuDOS Pharmaceuticals and AstraZeneca

1: Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B. Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. J Clin Oncol. 2011 Dec 27. [Epub ahead of print] PubMed PMID: 22203755.

2: Yamamoto N, Nokihara H, Yamada Y, Goto Y, Tanioka M, Shibata T, Yamada K, Asahina H, Kawata T, Shi X, Tamura T. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci. 2011 Dec 7. doi: 10.1111/j.1349-7006.2011.02179.x. [Epub ahead of print] PubMed PMID: 22145984.

3: Senra JM, Telfer BA, Cherry KE, McCrudden CM, Hirst DG, O'Connor MJ, Wedge SR, Stratford IJ. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther. 2011 Oct;10(10):1949-58. Epub 2011 Aug 8. PubMed PMID: 21825006; PubMed Central PMCID: PMC3192032.

4: Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011 Sep;12(9):852-61. Epub 2011 Aug 19. PubMed PMID: 21862407.

5: Sahin I, Ararat E, Altundag K. BRCA-deficient and triple negative breast cancers: is olaparib effective in both subtypes? J BUON. 2011 Jan-Mar;16(1):184-5. PubMed PMID: 21674877.

6: Sparidans RW, Martens I, Valkenburg-van Iersel LB, den Hartigh J, Schellens JH, Beijnen JH. Liquid chromatography-tandem mass spectrometric assay for the PARP-1 inhibitor olaparib in combination with the nitrogen mustard melphalan in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Jul 1;879(21):1851-6. Epub 2011 May 7. PubMed PMID: 21622034.

7: Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, Cassidy J. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs. 2011 May 18. [Epub ahead of print] PubMed PMID: 21590367.

8: Forster MD, Dedes KJ, Sandhu S, Frentzas S, Kristeleit R, Ashworth A, Poole CJ, Weigelt B, Kaye SB, Molife LR. Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer. Nat Rev Clin Oncol. 2011 May;8(5):302-6. Epub 2011 Apr 5. PubMed PMID: 21468130.

9: Khan OA, Gore M, Lorigan P, Stone J, Greystoke A, Burke W, Carmichael J, Watson AJ, McGown G, Thorncroft M, Margison GP, Califano R, Larkin J, Wellman S, Middleton MR. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer. 2011 Mar 1;104(5):750-5. Epub 2011 Feb 15. PubMed PMID: 21326243; PubMed Central PMCID: PMC3048218.

10: Molecule of the month. Olaparib. Drug News Perspect. 2010 Nov;23(9):606. PubMed PMID: 21152454.

11: Kortmann U, McAlpine JN, Xue H, Guan J, Ha G, Tully S, Shafait S, Lau A, Cranston AN, O'Connor MJ, Huntsman DG, Wang Y, Gilks CB. Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xenografts. Clin Cancer Res. 2011 Feb 15;17(4):783-91. Epub 2010 Nov 19. PubMed PMID: 21097693.

12: Hutchinson L. Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol. 2010 Oct;7(10):549. PubMed PMID: 20922827.

13: Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, Smith G, Powell JE, Rudzki Z, Kearns P, Moss PA, Taylor AM, Stankovic T. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010 Nov 25;116(22):4578-87. Epub 2010 Aug 25. PubMed PMID: 20739657.

14: Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):245-51. Epub 2010 Jul 6. PubMed PMID: 20609468.

15: Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):235-44. Epub 2010 Jul 6. PubMed PMID: 20609467.