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

Abstract

Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate singleagent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately doseproportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. Ó2017 AACR.

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

“…As reported in previous studies of rucaparib and other PARP inhibitors, 5, 6, 9, 10, 11 gastrointestinal side-effects, asthenia or fatigue, and myelosuppression were common treatment-emergent adverse events in the rucaparib group. Management of adverse events included supportive care and dose modifications (including treatment interruption or dose reduction).…”

PARP inhibitors: Clinical utility and possibilities of overcoming resistance

“…FDA approval of rucaparib (Clovis Oncology) was announced on December 19, 2016 based on the results of two multicenter randomized open label trials, Study 10 and ARIEL, parts 1 and 2 [18, 19]. The two phase (I/II) Study 10, reported in early 2017, enrolled 56 patients with g BRCA mutated platinum sensitive ovarian cancer with two to four lines of previous therapy.…”

“…The two phase (I/II) Study 10, reported in early 2017, enrolled 56 patients with g BRCA mutated platinum sensitive ovarian cancer with two to four lines of previous therapy. The phase II portion of Study 10 enrolled 42 patients, after establishing the phase I dose of 600 mg twice daily, and showed a 59.5% investigator-assessed overall response rate [18]. ARIEL 2 enrolled patients with g BRCA mutations and platinum-sensitive high grade ovarian carcinoma, and defined HR deficiency subgroups: BRCA mutant (deleterious germline or somatic), BRCA wild type with loss of heterozygosity (LOH) high, or BRCA wildtype with LOH low, using a cutoff of 14% or more genomic LOH for LOH high.…”

Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation

“…17,18 In this study, we assessed the efficacy and safety of rucaparib monotherapy in patients with locally advanced or metastatic PC with a known deleterious BRCA1/2 mutation.…”