CHICAGO – Women whose ovarian cancers harbor a BRCA mutation or have a similar genomic signature are most likely to benefit from the investigational agent rucaparib, suggest interim results of a phase II trial reported at the annual meeting of the Society of Gynecologic Oncology.
Investigators assessed activity of this novel oral PARP (poly-ADP-ribose) inhibitor in ARIEL2, A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. The study was sponsored by Clovis Oncology, manufacturer of rucaparib.
They also tested a biomarker of homologous recombination deficiency (HRD), which confers susceptibility to PARP inhibitors and is commonly seen in BRCA-mutated tumors, said Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and a professor at the University of Washington, Seattle.
Tumors were genomically profiled with next-generation sequencing, which picks up the loss of heterozygosity caused by HRD, whether specifically due to a BRCA mutation or to other molecular aberrations that give tumors a similar genomic signature.
Results in the first 121 evaluable patients showed that 25% had tumors with a BRCA mutation (a percentage capped in the study) and 42% had tumors that lacked such mutation but nonetheless had a BRCA-like signature, while 33% had tumors negative for the biomarker, Dr. Swisher reported.
The response rate to rucaparib according to RECIST (Response Evaluation Criteria In Solid Tumors) was 43% among 61 evaluable patients overall. But it varied significantly by HRD biomarker status: It was 65% in those with BRCA-mutated tumors and 40% in those with a BRCA-like signature, but only 8% in those with tumors negative for the biomarker (P less than .001).
The most common treatment-related adverse events were nausea, fatigue, and transient elevation of liver function tests. None of the patients stopped treatment because of toxicity.
“Rucaparib is active and well tolerated in high-grade ovarian cancer,” summarized Dr. Swisher.
“Comprehensive genomic analysis of the tumor based on a next-generation sequencing platform can prospectively identify ovarian cancer patients who respond to rucaparib, and it identifies both relevant BRCA mutations and a BRCA-like signature in one test,” she said. “The BRCA-like signature could have utility in other cancer types beyond ovarian cancer, potentially.”
She noted that ARIEL2 has recently been expanded to be a registration study for the treatment of patients with ovarian cancer who have had failure of three prior therapies, regardless of BRCA mutational status, and remains open for enrollment.
Investigators with the ARIEL program are refining the HRD biomarker, according to Dr. Swisher. “We will look at different cutoffs to see if we can get an even better cutoff for defining the BRCA-like cases. That biomarker will be locked down and tested prospectively in ARIEL3, which is the pivotal phase III, randomized, placebo-controlled study – recurrent, maintenance, platinum sensitive – that hopefully will be a registration study,” she elaborated.
Dr. Swisher disclosed that she had no relevant conflicts of interest. The trial was sponsored by Clovis Oncology.