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Background: Niraparib(N)is an oral,potent PARP1/2 inhibitor that induces synthetic lethality in BRCA1/2 deficient tumors.PARP is also implicated in transcription regulated by the androgen receptor(AR)and rearranged ETS genes; key targets in CRPC.Methods: Dose-escalation was enriched for BRCA1/2mutation carriers(BRCA-MCs).Two MTD expansion cohorts were undertaken in patients(pts)with sporadic high grade serous ovarian cancer(HGSOC)and CRPC.In CRPC pts,archival tissue and circulating tumor cells(CTC)were analyzed for PTEN deletion and ETS gene rearrangements.Results: 100 pts [ovary(49),CRPC(23),breast(12)others(16)],received N at 10 dose levels: 30mg to 400mg daily(od),continuously.Grade(G)4 thrombocytopenia was dose limiting at 400mg od; MTD was established at 300mg od.Drug-related toxicities were G1-2 reversible anemia(48%),fatigue(42%),nausea(42%),thrombocytopenia(35%),anorexia(27%),neutropenia(24%),constipation(23%),and vomiting(20%).PKs were dose proportional with a mean elimination t1/2of 40 hours.Peripheral blood mononuclear cells had >50%PARP inhibition from 80 mg od.gH2AX foci formation,a marker of DNA damage,was seen in CTCs.Antitumor activity occurred from 60mg od with RECIST and/or CA125 partial responses(PR)in 9/20(45%)BRCA-MC ovarian cancer pts and 2/4(50%)BRCA-MC breast cancer pts.Platinum-sensitive vs resistant BRCA-MC HGSOC response rate was 60%vs 33%with median time for responding pts of 429 and 340 days,respectively.In sporadic HGSOC,there were 2/3 PRs in platinum-sensitive pts,and 3/20 PRs plus 4/20 stable disease(SD)>16 weeks in platinum resistant pts.In CRPC,symptomatic benefit and SD >6 months(median 9 months)was seen in 9/21(43%)pts treated at MTD.CTC declines of >30%(median 80%; range 36%-92%)were observed in 7/10(70%)pts with evaluable CTC counts(≥5 cells/7.5mL blood).Conclusions: Niraparib was well tolerated and has promising antitumor activity in BRCA-MCs,sporadic HGSOC and CRPC.