Loss of genomic heterozygosity is a marker for the efficacy of rucaparib even in patients without BRCA 1 and 2 mutations, according to a poster presented Monday at the 2016 ASCO Annual Meeting.
Robert Coleman, MD
Loss of genomic heterozygosity is a marker for the efficacy of rucaparib even in patients withoutBRCA1 and 2 mutations, according to a poster presented Monday at the 2016 ASCO Annual Meeting.1
Researchers found that the biomarker was an effective predictor of response to the drug in high grade, recurrent ovarian cancer patients who received the experimental drug, a poly (ADP-ribose) polymerase (PARP) inhibitor, if adjusted slightly from the benchmark reached by the Cancer Genome Atlas.2
“Likelihood of response can be hard to measure if you’re just looking at a specific gene.BRCAregulates recombination, which is how major defects in DNA are fixed with high fidelity. So whenBRCAis mutated, you can’t fix these defects, and as they occur across entire genome, you see a loss of heterozygosity (LOH) which is diffuse across the genome,” explained Robert Coleman, MD, a professor in the Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Comprehensive Cancer Center.
“About 45% of those with wild-type BRCA genes exhibit a significant amount of LOH. Even though the major gene that fixes this is intact, there are other things that are not intact, otherwise you wouldn’t have a lot of LOH. We can’t say which gene is the one, because there may be a lot of genes contributing. The DNA repair mechanism is just not working right. But we already know that giving a PARP inhibitor to patients with the BRCA mutation yields a high response rate, so we wondered, ‘If we give the drug to BRCA wild-type patients, what happens?’”
Biomarker Improved by Slight Modification of Threshold
To find out, researchers classified 204 patients who received rucaparib in ARIEL2 (part one), a phase II study of the investigational drug, into three groups: those with the BRCA mutation, those without the mutation and with a low level of LOH, and those without the mutation but with a high level of LOH (NCT01891344).
In 40 subjects with the BRCA mutation, the response rate was 85% for those with germline mutations, and 75% for those with somatic mutations. The risk of disease progression was reduced by 73% in patients with the mutation. However, the risk of disease progression was reduced by only 38% in wild-type BRCA patients with high LOH who received rucaparib (using the cut-off of 14% LOH previously calculated by the Cancer Genome Atlas).
“We estimated the 14% LOH threshold based on historical controls in patients who had a response to platinum chemotherapy, although we were looking not at platinum, but a PARP inhibitor,” explained Coleman.
When the threshold for high LOH patients was refined to 16% LOH, the treatment was found to decrease the risk of progression by 49% (P<.001), and median progression-free survival (PFS) in high LOH patients was 7.2 months, up from 5.7 months using the 14% threshold, according to the researchers.
Part 1 of ARIEL2 completed enrollment in December 2014, and follow-up data was included in the poster through January 18 of this year. The median age was 65, and subjects had been treated with a median of 1 prior regimen. Three patients died due to disease progression.
All of the patients had high-grade cancer. “The tumors were most commonly serous, with lots of nuclear atypia, and a bizarre growth pattern in which the cells lose the ability to grow glandular structures,” Coleman noted.
“However, we’re not curing patients. Why? It could be that the cancer is not all sensitive at the same time. Or some tumors may first present with a mixture of sensitive and resistant cells. But over time, we keep selecting for more resistant cancers,” noted Coleman.
For part 2 of ARIEL2, researchers intended to recruit approximately 200 additional patients; accrual is expected to be complete within the next month or two. The cohort is intended to be more heavily pre-treated, seeking patients who have had 3 or 4 lines of treatment, according to Coleman.
Other ideas for future research include combination therapy, he added. “We could try to prevent resistance development with a strategy to allow for the cancer’s resistance mechanisms to be engaged, but we don’t have a home run strategy.”
Rucaparib has received breakthrough designation by the FDA, and the manufacturers will file an application for accelerated approval in the second quarter of this year, based on all of the drug’s data, but mostly in ovarian cancer, according to Coleman.
Coleman R, Swisher E, Oza A, et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: A phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC).J Clin Oncol34, 2016 (suppl; abstr 5540).
Watkins J, Irshad S, Grigoriadis A, et al. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.Breast Cancer Res.2014;16(3): 211.