• DOI:10.1056/NEJMoa0900212
• Corpus ID: 10051747

Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.

@article{Fong2009InhibitionOP,
  title={Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.},
  author={Peter C.C. Fong and David S. Boss and Timothy Anthony Yap and Andrew N. J. Tutt and Pei Jun Wu and Marja W. J. Mergui-Roelvink and Peter S. Mortimer and Helen C. Swaisland and Alan Lau and Mark J. O’Connor and Alan Ashworth and James Carmichael and Stanley B. Kaye and Jan H. M. Schellens and Johann S. de Bono},
  journal={The New England journal of medicine},
  year={2009},
  volume={361 2},
  pages={
          123-34
        }
}

• P. Fong, D. Boss, +12 authors J. D. de Bono
• Published 16 December 2009
• Medicine, Biology
• The New England journal of medicine

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.)