Rucaparib's Efficacy in Ovarian Cancer Determined With Novel Biomarker

Robert Coleman, MD

While BRCA status continues to be a predictive indicator of response to rucaparib for patients with ovarian cancer, loss of genomic heterozygosity was shown to also be an effective biomarker for predicting outcomes.

The confirmed response rate with rucaparib was 29% in those with high levels of loss of heterozygosity (LOH) compared with just 10% in those with low LOH, according to results of a study presented at the 2016 ASCO Annual Meeting.¹ The confirmed objective response rate (ORR) with the PARP inhibitor was the highest in those with BRCA mutations. In this group, responses were seen in 70% to 85% of patients with ovarian cancer.

In the trial, which was labeled ARIEL2, researchers classified 204 patients into three groups, based upon their genetics. The groups contained those with the BRCA mutation (n = 39; germline or somatic), those without the mutation and with a low level of LOH (n = 83), and those without the mutation but with a high level of LOH (n = 82). 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.

The ORR was 85% for those with germline BRCA mutations, and 74% for those with somatic mutations. Median progression-free survival (PFS) was 12.8 months, 5.7 months, and 5.2 months, for the BRCA-mutant, BRCA wild-type/LOH-high, and BRCA wild-type/LOH-low groups, respectively.

Those in the BRCA-mutant group experienced a 73% reduction in the risk of progression compared with the BRCA wild-type/LOH-low population (HR, 0.27; 95% CI, 0.16-0.44; P <.001). Compared with this same group, the BRCA wild-type/LOH-high arm showed a 38% reduction in the risk of progression (HR, 0.62; 95% CI, 0.42-0.90; P = .01).

“Likelihood of response can be hard to measure if you’re just looking at a specific gene. BRCA regulates recombination, which is how major defects in DNA are fixed with high fidelity. So when BRCA is mutated, you can’t fix these defects, and as they occur across entire genome, you see a LOH which is diffuse across the genome,” said Coleman. “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."

For the primary assessment, LOH was established using a cutoff of 14% that was previously calculated by the Cancer Genome Atlas.² Subsequent analyses explored a higher cutoff of 16%.

“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%, the treatment was found to decrease the risk of progression by 49% compared with the LOH-low group (P <.001). With the new criteria applied, the median PFS was 12.8 months, 7.2 months, and 5.0 months, for the BRCA-mutant, BRCA wild-type/LOH-high, and BRCA wild-type/LOH-low groups, respectively.

The most common treatment-emergent adverse events (AEs) with rucaparib were nausea (80%), asthenia (78%), fatigue (78%), constipation (46%), vomiting (44%), and dysgeusia (43%). The most common grade 3/4 treatment-emergent AEs were anemia (21%), decreased hemoglobin (21%), and ALT/AST elevations (12%).

“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 intend to recruit approximately 200 additional patients. The cohort is enrolling heavily pretreated patients following 3 or 4 lines of treatment, according to Coleman. The phase III ARIEL3 trial is also investigating rucaparib in patients with homologous repair deficiency detected using next-generation sequencing.

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 have filed a new drug application. The FDA is scheduled to make a decision on the application later this year or in the first quarter of 2017.

References

1. 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 Oncol 34, 2016 (suppl; abstr 5540).
2. 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.

“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,” explained Robert Coleman, MD, a professor in the Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Comprehensive Cancer Center. "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?’”