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Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor.
Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation.
Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens.
Conclusions Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373
[ClinicalTrials.gov]
.)
Source Information
From the Drug Development Unit, Royal Marsden National Health Service (NHS) Foundation Trust and the Institute of Cancer Research, Sutton, Surrey (P.C.F., T.A.Y., S.B.K., J.S.B.); the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research (A.T., P.W., A.A.), and the Breakthrough Breast Cancer Research Unit at King's College London, Guy's Campus (A.T., P.W.) — both in London; KuDOS Pharmaceuticals, Cambridge (P.M., A.L., M.J.O., J.C.); and AstraZeneca, Macclesfield (H.S.) — all in the United Kingdom; and the Netherlands Cancer Institute, Amsterdam (D.S.B., M.M.-R., J.H.M.S.); and Department of Pharmaceutical Sciences, Utrecht University, Utrecht (J.H.M.S.) — both in the Netherlands.
This article (10.1056/NEJMoa0900212) was published on June 24, 2009, at NEJM.org.
Address reprint requests to Dr. de Bono at the Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey SM2 5PT, United Kingdom, or at johann.de-bono{at}icr.ac.uk.
Related Letters:
Inhibition of Poly(ADP-Ribose) Polymerase in BRCA Mutation Carriers
Li S., Yap T. A., Kaye S. B., de Bono J. S.
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N Engl J Med 2009;
361:1707-1708, Oct 22, 2009.
Correspondence
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