In preclinical studies inhibition of poly(ADP-ribose) polymerase (PARP) has been shown to specifically kill cancer cells that have defects in their ability to repair DNA damage by the homologous recombination pathway — as is the case for patients with mutations in BRCA1 or BRCA2 — through a synthetic lethal effect. Phase I data on the PARP inhibitor olaparib in patients with mutations in BRCA1 or BRCA2 have now been published in the New England Journal of Medicine.

The trial enrolled 60 patients with advanced solid tumours, 22 of whom were known BRCA1 or BRCA2 mutation carriers and 1 of whom had a suspected mutation but declined testing. The adverse effect profile of olaparib was acceptable. PARP inhibition was confirmed in pharmacodynamic studies using peripheral-blood mononuclear cells and plucked eyebrow hair follicles. Of the 23 patients with known or suspected BRCA1 or BRCA2 mutations, responses could be evaluated in 21. Of these, 19 had ovarian, breast or prostate cancer; clinical benefit was seen in 12 (63%).

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