Update on PARP1 inhibitors in ovarian cancer
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).
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