Rucaparib significantly prolongs progression-free survival among patients with BRCA-mutant or BRCA wild-type and high loss of heterozygosity (LOH), recurrent, platinum-sensitive, high-grade ovarian carcinomas, according to a study published in The Lancet Oncology.1
Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated activity in ovarian carcinomas with homologous recombination deficiency. In addition to BRCA1 and BRCA2 mutations, researchers hypothesized that genomic LOH might also predict response to treatment with PARP inhibitors.
To determine if tumor genomic LOH is associated with response to rucaparib, researchers developed ARIEL2 (ClinicalTrials.gov Identifier: NCT01891344), an international, 2-part, open-label, phase 2 trial. In part 1, investigators enrolled 192 patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma.
Participants were classified into 1 of 3 predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis: BRCA-mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). Patients received rucaparib orally twice daily continuously in 28-day cycles until disease progression or unacceptable toxicity.
Treatment with rucaparib significantly reduced the risk of progression or death by 73% in the BRCA-mutant group (hazard ratio, 0.27; 95% CI, 0.16-0.44; P < .0001) and by 38% in the LOH high subgroup (hazard ratio, 0.62; 95% CI, 0.42-0.90; P = .011) compared with the LOH low subgroup.
Median progression-free survival after rucaparib therapy was 12.8 months (95% CI, 9.0-14.7) in the BRCA-mutant subgroup, 5.7 months (95% CI, 5.3-7.6) in the LOH high subgroup, and 5.2 months (95% CI, 3.6-5.5) in the LOH low subgroup.
The most common grade 3 or worse treatment-emergent adverse events were anemia in 22% of patients, and elevations in alanine aminotransferase or aspartate aminotransferase in 12%. No treatment-related deaths were reported.
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The findings suggest that evaluation of tumor LOH can help to identify patients with BRCA wild-type platinum-sensitive ovarian carcinomas who might benefit from treatment with rucaparib.
- Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 Nov 28. doi: 10.1016/S1470-2045(16)30559-9 [Epub ahead of print]