The clinical development of
PARP inhibitors for the treatment of
tumors deficient in BRCA1 or BRCA2 is based on the concept of synthetic lethality. From the initial proof of concept study with the PARP1 inhibitor
olaparib (
AZD2281) in BRCA mutation carriers, in which 28% of
ovarian cancer patients achieved an objective response, the target population of ovarian patients potentially sensitive to treatment with
PARP inhibitors has greatly increased. Objective responses have been observed in both
platinum-sensitive and
platinum-resistant BRCA mutation carriers but, more recently, also in BRCA negative 'BRCAness' patients, those with no BRCA mutations but with a dysfunction of the homologous recombination (HR) system, which makes them more sensitive to the
antitumor agents which cause double strand breaks of
DNA. The recent results achieved with
olaparib, given as maintenance in
platinum sensitive recurrent high grade serous
ovarian cancer, in response after reinduction with
platinum, confirm the antitumor effect of single agent
olaparib in BRCAness patients. Main topics of investigations in this field are the identification of BRCAness phenotype and the definition of tests to identify BRCAness patients. More in general, additional preclinical studies are needed to further improve clinical results in order to define the optimal regimen of combination with PARP1 inhibitor and cytotoxics or molecular targeted agents (sequence of administration, interval between dosing of the agents,
duration of treatment).