title: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.
abstract: 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.
authors.affiliation: Northern Institute for Cancer Research and the Northern Centre for Cancer Care, Newcastle Freeman Hospital Newcastle, Newcastle 0191 2139386, UK.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drew
authors.affiliation: UCL Cancer Institute, CR-UK and UCL Cancer Trials Centre, 90 Tottenham Court Road, London W1T 4TJ, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ledermann
authors.affiliation: St James's University Hospital, Cancer Research UK Clinical Cancer Centre in Leeds, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Hall
authors.affiliation: University of Birmingham, School of Cancer Sciences, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rea
authors.affiliation: Beatson West of Scotland Cancer Centre, Medical Oncology 1053 Great Western Road, Glasgow G12 0YN, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Glasspool
authors.affiliation: Derriford Hospital Plymouth Oncology Centre, Plymouth, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Highley
authors.affiliation: University of Manchester, Paterson Institute for Cancer Research, Translational Angiogenesis Group, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Jayson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle, UK.
authors.forename: Julieann
authors.initials: J
authors.lastname: Sludden
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle, UK.
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle, UK.
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.affiliation: Cancer Research UK, Drug Development Office, The Angel Building, 407 St John Street, London EC1V 4AD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Halford
authors.affiliation: Cancer Research UK, Centre for Drug Development Drug Development, Angel Building, London EC1V 4AD, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Acton
authors.affiliation: Cancer Research UK, Centre for Drug Development Drug Development, Angel Building, London EC1V 4AD, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Backholer
authors.affiliation: Cancer Research UK, Centre for Drug Development Drug Development, Angel Building, London EC1V 4AD, UK.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mangano
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Boddy
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Curtin
authors.affiliation: Northern Institute for Cancer Research and the Northern Centre for Cancer Care, Newcastle Freeman Hospital Newcastle, Newcastle 0191 2139386, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D011379:Prognosis; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib