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

• Published in: British journal of cancer 2016-03, Vol.114 (7), p.723-730
• Main Authors: Drew, Yvette, Ledermann, Jonathan, Hall, Geoff, Rea, Daniel, Glasspool, Ros, Highley, Martin, Jayson, Gordon, Sludden, Julieann, Murray, James, Jamieson, David, Halford, Sarah, Acton, Gary, Backholer, Zoe, Mangano, Raffaella, Boddy, Alan, Curtin, Nicola, Plummer, Ruth
• Format: Article
• Language: English
• Subjects: 631/92/436/2388; 692/308/2779/109/1941; 692/699/67/1347; 692/699/67/1517/1709; Adult; Aged; Biomedical and Life Sciences; Biomedicine; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Clinical Study; Clinical trials; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Epidemiology; Female; Follow-Up Studies; Genomes; Germ-Line Mutation - genetics; Heterozygote; Humans; Indoles - pharmacokinetics; Indoles - therapeutic use; Medical research; Middle Aged; Molecular Medicine; Mutation; Neoplasm Staging; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Pharmacodynamics; Pharmacokinetics; Poly(ADP-ribose) Polymerase Inhibitors - pharmacokinetics; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prognosis; Tissue Distribution; Toxicity; Tumors; Young Adult
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2016.41

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.