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

Abstract (PubMed)

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, an oral PARP inhibitor, in 60 patients with advanced solid tumors carrying a BRCA1 or BRCA2 mutation. No objective responses were observed at doses of 10 mg to 100 mg per day. At doses of 100 mg twice daily or more, tumor responses were observed in 12 of 60 patients (including BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancers). Pharmacokinetic and pharmacodynamic data indicated that the drug inhibited PARP activity in surrogate tissue and in tumors. Common adverse effects were mild and included fatigue, nausea, and vomiting. This study confirms the proof-of-concept that PARP inhibition provides selective tumor-cell killing in BRCA mutation carriers.