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 BRCA1/2 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 prop...