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  • Benny Miles posted an update 3 years, 1 month ago

    Germline BRCA1 and BRCA2 mutations have been identified in approximately 15% of all EOCs, which is a low estimation if high-grade serous (HGS) histology (up to 22.6%) is considered. In general, somatic BRCA1 and BRCA2 mutations are estimated to occur in 7% of all EOC[60]�C[62]. The clinical development of PARP inhibitors has been accelerated again following encouraging data on their efficacy CP868596 in EOC treatment. Given their demonstrated activity as single agents and toxicity profiles, including myelosuppression and gastrointestinal adverse effects, most studies focus on maintenance treatment after chemotherapy rather than combinations with antineoplastic drugs. Olaparib is certainly the best known PARP inhibitor, although a number of agents in the same class are currently under evaluation. Three phase II trials testing olaparib in different settings have been already published[63]�C[65], and a phase III FDA registration trial is ongoing (ClinicalTrials.gov GW-572016 datasheet identifier: NCT01844986). In the phase II trial by Ledermann et al.[63], olaparib, which is given as a maintenance treatment after platinum-based chemotherapy, was compared with placebo in patients with platinum-sensitive, recurrent, HGS ovarian cancer. A total of 265 women were recruited, and PFS, which was the primary endpoint, was found to be significantly longer in the experimental arm (median PFS, 8.4 versus 4.8 months; HR for progression or death, 0.35; 95% CI = 0.25�C0.49; P < 0.001). Furthermore, the ASCO 2013 data on the subgroup of patients harboring a BRCA mutation, either germline or somatic, showed that this population had the greatest benefit from maintenance with olaparib (median PFS, 11.2 versus 4.1 months; HR = 0.17, 95% CI = 0.09�C0.32,?P < 0.001)[66]. An ongoing phase III trial, the SOLO 1, is focused on germline BRCA mutation carriers with newly diagnosed EOC; olaparib maintenance is compared with placebo after platinum-based chemotherapy, again using PFS as the primary endpoint (ClinicalTrials.gov identifier: NCT01844986). The SOLO 2 trial (ClinicalTrials.gov identifier: NCT01874353) uses the same design (germline BRCA mutations carriers, olaparib maintenance versus placebo after platinum-based chemotherapy), but PTPRJ in a recurrent setting (only platinum-sensitive relapse). Other PARP inhibitors are also under development, namely niraparib (ClinicalTrials.gov identifier: NCT01847274) and rucaparib (ClinicalTrials.gov identifier: NCT01891344), both of which are currently being tested in platinum-sensitive recurrence. Future Perspectives Since the entry of the carboplatin-paclitaxel doublet?into routine clinical practice, a relative standstill in the literature has come to pass. However, within the past 5 years, several positive trials have begun to suggest possible new therapeutic options.