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.

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

“…Recently, Drew et al (2016) examined the efficacy of another PARPi, rucaparib, in advanced breast and ovarian cancers. Rucaparib broadly targets PARP-1 and PARP-2 and has also been shown to have some inhibitory effect on the activity of Tankyrase1 and Tankyrase2 (PARP-5a and PARP-5b) (Thomas et al 2007;Haikarainen et al 2014).…”

“…Rucaparib broadly targets PARP-1 and PARP-2 and has also been shown to have some inhibitory effect on the activity of Tankyrase1 and Tankyrase2 (PARP-5a and PARP-5b) (Thomas et al 2007;Haikarainen et al 2014). Rucaparib administered in continuous doses was shown to be effective against germline BRCA mutant cancers in stage II clinical trials (Drew and Calvert 2008;Brown et al 2016;Drew et al 2016).…”

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

“…An open-label, phase II study investigated intermittent dosing of intravenous rucaparib (5 days of a 21-day cycle), as well as intermittent and continuous dosing of oral rucaparib (7,14, or 21 days of a 21-day cycle) in small cohorts of patients with advanced ovarian or breast cancer associated with a germline BRCA1/2 mutation (33). This study provided evidence that continuous dosing of oral rucaparib led to a higher rate of response than intermittent intravenous dosing (response rate, 18% vs. 2%).…”

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

“…Inhibitors of PARP improve the efficiency and selectivity of DNA-damaging agents (Calabrese et al 2004). The PARP inhibitors olaparib and rucaparib have entered clinical trials for several cancer types, either as monotherapy or in combination with cytotoxic drug therapy Tutt et al 2010;Plummer et al 2013;Bendell et al 2015;Mateo et al 2015;Drew et al 2016). Radiosensitization has been demonstrated in human and rodent cell lines and in experimental tumors by treatment with PARP inhibitors (Virag & Szabo 2002;Brock et al 2004;Calabrese et al 2004), indicating their potential as components of combination therapy.…”