In part 1 of the phase II ARIEL2 trial reported in The Lancet Oncology, Elizabeth M. Swisher, MD, of the University of Washington, and colleagues found that the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib was associated with prolonged progression-free survival among patients with relapsed platinum-sensitive high-grade ovarian carcinoma who had BRCA-mutant or BRCA wild-type loss of heterozygosity–high tumors vs BRCA wild-type loss of heterozygosity–low tumors.
In the open-label study, 206 women from 49 sites in Australia, Canada, France, Spain, the UK, and the United States were enrolled between October 2013 and December 2014. At data cutoff, 204 patients had received rucaparib; 192 could be classified into three predefined homologous recombination deficiency subgroups: BRCA mutant (n = 40), BRCA wild-type loss of heterozygosity–high (≥ 14% genomic loss of heterozygosity; n = 82), or BRCA wild-type loss of heterozygosity–low (n = 70). Treatment consisted of oral rucaparib at 600 mg twice a day for continuous 28-day cycles until disease progression or treatment discontinuation for other reasons. The primary endpoint was progression-free survival in all classified patients. A trial extension (part 2) is ongoing.
Outcomes by Subgroup
Median duration of treatment was 5.7 months. Median progression-free survival was 12.8 months (95% confidence interval [CI] = 9.0–14.7 months) in the BRCA-mutant group (hazard ratio [HR] = 0.27, P < .0001, vs loss of heterozygosity–low group), 5.7 months (9.5% CI = 5.3–7.6 months) in the loss of heterozygosity–high group (HR = 0.62, P = .011, vs loss of heterozygosity–low group), and 5.2 months (95% CI = 3.6–5.5 months) in the loss of heterozygosity–low group. Progression-free survival at 12 months was 50% and 28% vs 10%, respectively.
The most common grade ≥ 3 adverse events were anemia or decreased hemoglobin (22%) and elevated alanine transaminase or aspartate transaminase levels (12%). The most common serious adverse events included small intestinal obstruction (5%), malignant neoplasm progression (5%), and anemia (4%). Three patients died during the study, with no deaths considered to be related to treatment.
The investigators concluded: “In patients with BRCA mutant or BRCA wild-type and [loss of heterozygosity] high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type [loss of heterozygosity] low carcinomas. Our results suggest that assessment of tumour [loss of heterozygosity] can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours.”
The study was funded by Clovis Oncology, the U.S. Department of Defense Ovarian Cancer Research Program, a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research grant, and a V Foundation Translational Award.