Final results of the phase I trial of niraparib (MK4827), a poly(ADP)ribose polymerase (PARP) inhibitor incorporating proof of concept biomarker studies and expansion cohorts involving <i>BRCA1/2</i> mutation carriers, sporadic ovarian, and castration resistant prostate cancer (CRPC).

2513 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 t 1/2 of 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. Clinical trial information: NCT0074902.