BACKGROUND: Rucaparib is an orally available potent selective small-molecule 
inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces 
synthetic lethality in cancer cells defective in the homologous recombination 
repair pathway including BRCA-1/2. We investigated the efficacy and safety of 
single-agent rucaparib in germline (g) BRCA mutation carriers with advanced 
breast and ovarian cancers.
METHODS: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 
mutation carriers with advanced breast and or ovarian cancer, WHO PS 0-1 and 
normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were 
assessed, using a range of dosing schedules, to determine the safety, 
tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and 
pharmacokinetic (PK) profiles.
RESULTS: Rucaparib was well tolerated in patients up to doses of 480 mg per day 
and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single 
doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an 
objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients 
achieved stable disease for ⩾12 weeks and 3 patients maintaining disease 
stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose 
levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had 
ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST 
complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, 
with a median duration of response of 179 days (range 84-567 days).
CONCLUSIONS: Rucaparib is well tolerated and results in high levels of PARP 
inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is 
active in gBRCA-mutant ovarian cancer and this activity correlates with 
platinum-free interval. The key lessons learned from this study is that 
continuous rucaparib dosing is required for optimal response, the recommended 
phase 2 dose (RP2D) for continuous oral scheduling has not been established and 
requires further exploration and, thirdly, the use of a PD biomarker to evaluate 
dose-response has its limitations.