Managing Editor, OncLive®
Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. She helped launch the rapidly growing infectious disease news resource Contagion, strengthened the Rare Disease Report, of HCPLive, and now serves as the main digital news writer for OncLive. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email: email@example.com
RAD51C and RAD51D mutations and high-level BRCA1 promotor methylation are predictive of response to rucaparib in patients with recurrent ovarian cancer, while genomic scars linked with homologous recombination deficiency is predictive of response only in those with platinum-sensitive disease.
RAD51C and RAD51D mutations and high-level BRCA1 promotor methylation are predictive of response to rucaparib (Rubraca) in patients with recurrent ovarian cancer, while genomic scars linked with homologous recombination deficiency (HRD) is predictive of response only in those with platinum-sensitive disease, according to data from a post-hoc exploratory biomarker analysis of the phase 2 ARIEL2 trial (NCT01891344).1
“Given its general tolerability and efficacy…we propose that the administration of rucaparib, as active treatment, should be considered in earlier lines of therapy, before the emergence of platinum resistance,” the study authors wrote.
Platinum sensitivity was a strong predictor of response to rucaparib in a population of patients who were naïve to PARP inhibitors, particularly subgroups who had disease that was BRCA-mutated or BRCA wild-type with high loss of heterozygosity (LOH). HRD mechanisms like BRCA mutation, RAD51C/D alterations and high BRCA1 promoter methylation were shown to result in sensitivity to both platinum treatment and rucaparib.
“Alterations in RAD51C and RAD51D correlated with meaningful clinical activity of rucaparib similar to that of BRCA-mutated high-grade ovarian cancer [HGOC],” the study authors added. “Therefore, we propose utilizing panels incorporating RAD51C/D when considering targeted therapies. Importantly, we previously showed that reversion mutations also occur in RAD51C/D as a resistance mechanism, supporting their essential role in generating synthetic lethality with PARP inhibitors.”
Additionally, investigators demonstrated that high-level methylation of the BRCA1 promoter proved to be a strong biomarker of sensitivity to the PARP inhibitor. Those who had this modification or tumors that harbored RAD51C/D had a progression-free survival (PFS) that proved to be comparable to those with BRCA-mutated HGOC who received rucaparib.
It has been known that genetic, epigenetic, and genomic biomarkers can potentially be indicative of HRD; these markers can help to select which patients are at a higher likelihood to respond to PARP inhibitors.
Germline and somatic BRCA1 and BRCA2 mutations have served as well-defined biomarkers of response for these agents spanning several cancer types, such as breast, ovarian, pancreatic, and prostate. Although genes in the homologous recombination repair (HRR) pathway like PALB2, RAD51C, and RAD51D have previously been linked with better response to rucaparib and other PARP inhibitors, the extent to which these genes contribute to drug sensitivity has been largely unclear.
Moreover, patients with BRCA-wildtype HGOC and high LOH have been shown to benefit more from rucaparib than those with low LOH. Although high LOH has been linked with better responses to platinum treatment and other PARP agents, genomic scars in HRD cancer cells make this an imperfect marker for sensitivity to this class of agents.
In the international, open-label, phase 2 ARIEL2 trial was done in 2 parts. In the first part, investigators examined rucaparib in patients with platinum-sensitive HGOC who had received 1 or more chemotherapy regimens.2 A total of 204 patients were enrolled to part 1 of the trial and they received a twice-daily dose of 600 mg for a continuous 28-day treatment cycle.
Of these patients, 192 were stratified into 3 groups based on their HRD status: 20.8% had BRCA-mutant disease, 42.8% had LOH-high disease, and 36.4% had LOH-low disease. The median PFS in these subgroups with rucaparib was 12.8 months, 5.7 months, and 5.2 months. The PFS was determined to be significantly longer in those who fell in the BRCA-mutant subset (HR, 0.27; 95% CI, 0.16-0.44; P <.0001) and in the LOH-high subset (HR, 0.62; 95% CI, 0.42-0.90; P = .011) vs the LOH-low subset.
Part 2 of the trial enrolled patients with disease that was sensitive, resistant, or refractory to platinum therapy, who had received 3 to 4 prior chemotherapies. A total of 287 patients were enrolled to part 2 of the trial and they were again divided into 1 of 3 HRD subgroups: those with BRCA-mutated disease (n = 138), those with BRCA wild-type LOH-high disease (n = 156), and those with BRCA wild-type LOH-low disease (n = 168).
Results indicated that the objective response rate (ORR) with rucaparib, which was the primary end point of the trial, was 31.0% (95% CI, 21.3%-42.0%), 6.8% (95% CI, 2.3%-15.3%), and 5.6% (95% CI, 2.1%-11.8%) in the 3 subgroups, respectively. Notably, durable responses were observed across the HRD subgroups analyzed.
In the post-hoc biomarker analysis, investigators utilized the dataset of archival tissue samples and screening biopsies collected from patients on both parts of the trial to examine the link between molecular characteristics and outcomes in participants, as well as to determine mechanisms of sensitivity and resistance to rucaparib.
Additional results demonstrated that both ORR and PFS different significantly among the subgroups, with those in the BRCA-mutated group experiencing better outcomes than the other 2 groups. Here, the median PFS was 7.8 months, and the ORR with rucaparib was 45.7% (95% CI, 37.2%-54.3%).
In the BRCA wild-type/LOH-high disease group and the BRCA wild-type/LOH-low disease group the median PFS was 4.3 months and 4.0 months, respectively; in these 2 groups, rucaparib elicited an ORR of 16.7% (95% CI, 11.2%-23.5%) and 7.7% (95% CI, 4.2%-12.9%), respectively.
Moreover, among patients in the BRCA-mutated group who were noted to be sensitive to their most recent line of platinum therapy received, the median PFS was 9.4 months, and the ORR was 64.9%, while patients who were refractory to their last platinum treatment had a significantly worse PFS and OS, at a median of 7.2 months (HR, 0.44; 95% CI, 0.30-0.63; P = <.0001) and an ORR of 23.4% (95% CI, 13.8%-35.7%; P <.0001).
Additionally, among those in the BRCA wild-type LOH-high disease subgroup who were platinum sensitive yielded better outcomes than those in the subgroup who were either platinum resistant or refractory in terms of PFS (HR, 0.46; 95% CI, 0.33-0.65) and ORR (95% CI, 0.9%-11.5%) and those in the BRCA wild-type LOH-low subgroups, irrespective of platinum status.
As such, investigators noted that genomic scarring is a good predictor of sensitivity to the PARP inhibitor prior to cross resistance, but LOH-low disease may lack HRD mechanisms necessary to sensitize these tumors to PARP inhibitors. As such, even those in this subgroup without previous exposure to platinum treatment still do not derive significant efficacy from rucaparib.
“Rucaparib efficacy in BRCA-mutated and BRCA wild-type/LOH-high but not BRCA wild-type/LOH-low HGOC was better for patients with platinum-sensitive disease who had received 1 or 2 prior therapies than those who had 3 or 4 prior chemotherapy regimens with predominantly platinum-resistant/refractory disease,” the authors noted. “These observations suggest that platinum sensitivity and fewer lines of prior platinum treatments are both linked to better outcomes on rucaparib in HRD-associated HGOC.”
Investigators also examined the link between BRCA mutational status and response to PARP inhibitors by taking a closer look at HRR gene mutational status and response to rucaparib. Twenty-eight percent of patients (n = 138/491) had deleterious or germline somatic BRCA mutations and ORRs in these agents proved to be similar to what had previous analyses in these subgroups of patients, at 48.2% and 45.5%, respectively. When examining HRR genes beyond BRCA, investigators did not find differences in median PFS and ORR in those who had BRCA wild-type disease associated with a HRR gene mutation vs those without a HRR gene mutation.
In light of prior evidence indicating that PALB2, RAD51C, and RAD51D mutations have been associated with sensitivity to PARP inhibitors, investigators decided to take a closer look. Seven patients had a deleterious RAD51C/D mutation, while no patients harbored a PALB2 mutation.
High responses with rucaparib were observed in the RAD51C/D-mutated subset, at 71.4% (95% CI, 29.0%-96.3%). Data from a multivariate analysis also determined that this mutation was a significant predictor of ORR with rucaparib. The median PFS in this subgroup was comparable to the benefit seen in the BRCA-mutant subgroup, at 11.0 months and 7.8 months, respectively (HR, 1.52; 95% CI, 0.67-3.44; P = .32). Notably, because 4 of the 7 patients whose tumors harbored this mutation had previously received 3 or more lines of chemotherapy, investigators concluded that rucaparib has the potential to be highly effective in this subgroup, even in those who are receiving it in later lines.
Investigators did not identify any difference in PFS in patients with BRCA wild-type disease who were examined for HRD-associated epigenetic events leading to rucaparib sensitivity based on either archival or screening methylation status, which indicates that the presence of methylation alone at the 2 promoters is not a biomarker for outcomes with the PARP inhibitor.
Although archival BRCA1 methylation levels were not linked with differential PFS with rucaparib, PFS outcomes were more favorable for patients with BRCA wild-type HGOC that had high BRCA1 methylation right before rucaparib initiation vs those with disease that was unmethylated or had low levels of methylation.
“Overall, our analysis highlights significant overlap between molecular mechanisms resulting in platinum and PARP inhibitor sensitivity and the extent of cross resistance that exists between these 2 drug classes,” the study authors concluded. “In addition to BRCA mutations, RAD51C/D mutations and high-level BRCA1 promoter methylation are strong predictors of sensitivity to a PARP inhibitor.”