The US Food and Drug Administration approved the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib (Rubraca®, Clovis Oncology, Inc., Boulder, CO) last December as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian carcinoma who have been treated with two or more chemotherapies. The US approval of rucaparib was supported by integrated data from the Study 10 (NCT01482715) and ARIEL2 (NCT01891344) clinical trials.
The phase 2 ARIEL2 study is an ongoing two-part trial designed to examine the efficacy of rucaparib monotherapy as treatment in patients with ovarian carcinoma. Part 1 of ARIEL2 is complete and results indicated that rucaparib provided a progression-free survival benefit to patients with platinum-sensitive ovarian carcinoma with a deleterious BRCA1 or BRCA2 (BRCA1/2) mutation (germline and/or somatic) or wild-type BRCA1/2 and a high degree of genomic loss of heterozygosity (LOH), a hallmark of DNA-repair defects, when compared to patients with ovarian carcinoma with wild-type BRCA1/2 and a low degree of genomic LOH. Part 2 of ARIEL2 is ongoing and aims to examine the efficacy of rucaparib in patients with platinum-sensitive, -resistant, or -refractory ovarian carcinoma who have received three to four prior chemotherapies. My colleague Dr. Gottfried E. Konecny and I recently provided an update of ARIEL2 data in two presentations at the Society of Gynecologic Oncologist’s (SGO’s) 2017 Annual Meeting on Women’s Cancer held March 12–15.
I presented updated data from ARIEL2 Part 1 that further examined responses observed in patients without a BRCA1/2 mutation. Patients with wild-type BRCA1/2 tumors that were found to harbor a mutation in the homologous recombination gene RAD51C responded to rucaparib; three of four patients had a partial response with more than 8 months of progression-free survival (PFS). One patient with a mutation in NBN had a complete response, with a PFS of 10.3 months. Three patients with a CDK12 mutation were identified, two of whom had long, durable responses (16.7 and 29.3 months). Although not directly involved in DNA repair, CDK12 is involved in RNA splicing, and its loss leads to down-regulation of genes involved in DNA repair, potentially resulting in homologous recombination deficiency.
Analysis was also performed to determine the promoter hypermethylation status of BRCA1 and RAD51C in archival and pretreatment tumor samples of patients from ARIEL2 Part 1 (n=165). Promoter methylation of these two genes has been associated with decreased gene expression in ovarian carcinoma. BRCA1 and RAD51C methylation and mutation were shown to be mutually exclusive, with a higher proportion of BRCA1 (12.7%) versus RAD51C (2.4%) methylated tumors detected. A clear association between BRCA1 and RAD51C methylation and high genomic LOH was identified in a correlation analysis. More than half of the patients with BRCA1 or RAD51 methylated tumors achieved a confirmed response to rucaparib (52.4% and 75.0%, respectively). In patients with paired archival and pretreatment biopsies, a gain of BRCA1 methylation from archival to pretreatment biopsy was rarely observed (1/77; 1.3%), but loss of BRCA1 methylation was observed in 4 of 13 cases (30.8%). This suggests that loss of BRCA1 methylation is common after exposure to platinum chemotherapy and that pretreatment biopsies would provide the best information to predict PARP inhibitor sensitivity for this biomarker. These new analyses support the use of routine sequencing of high-grade ovarian carcinoma that could identify at least 10% to 15% of cases with somatic mutations and 20% with germline mutations that are likely to respond to PARP inhibition. Examination of the promoter methylation status of BRCA1 and RAD51C may also be useful in identifying patients who may respond to PARP inhibition.
Dr. Konecny presented an integrated analysis of patients from ARIEL2 Parts 1 and 2 who had high-grade ovarian carcinoma with a germline or somatic BRCA1/2 mutation (n=134). Patients enrolled in ARIEL2 Part 1 had received at least one prior platinum-based chemotherapy and had platinum-sensitive ovarian carcinoma; patients enrolled in ARIEL2 Part 2 had received three to four prior chemotherapies and had platinum-sensitive, -resistant, or -refractory ovarian carcinoma. The objective response rate among patients with BRCA1/2-mutant ovarian carcinoma was greatest in those with platinum-sensitive disease, ranging from 52% in patients who had received at least three prior chemotherapies to 86% in those who received two prior lines of chemotherapy. Median PFS was 12.7 months in patients with platinum-sensitive, BRCA1/2-mutant ovarian carcinoma versus 7.3 months and 5.0 months in those with platinum-resistant and platinum-refractory BRCA1/2-mutant ovarian carcinoma, respectively. Among patients with platinum-sensitive tumors who had received platinum-based chemotherapy as their last prior treatment, median PFS was longest (25.1 months) in those with a progression-free interval of at least 18 months. The safety profile for patients in this integrated analysis was consistent with that previously reported for the overall ARIEL2 Part 1 population.
Secondary somatic mutations restoring BRCA1/2 function have been reported as a mechanism of platinum resistance. Thus as part of this integrated analysis, the presence of secondary BRCA1/2 mutations was examined in patients with platinum-resistant or -refractory ovarian carcinoma using next-generation sequencing of screening tumor biopsies and/or circulating tumor DNA. Secondary somatic mutations were detected in eight of 55 samples. Median PFS was shorter for patients with a secondary BRCA1/2 mutation (1.7 months) compared to those without (7.3 months).
These updated analyses demonstrate the effectiveness of rucaparib as a treatment for ovarian carcinoma and provide further insight into the subsets of patients who may receive the greatest benefit from treatment. A randomized, phase 3, confirmatory study investigating single-agent rucaparib versus standard-of-care chemotherapy is ongoing in patients with relapsed BRCA1/2-mutant (germline or somatic) high-grade ovarian carcinoma (ARIEL4; NCT02855944).
Conflict of interest statementE.M. Swisher reports a grant from the Department of Defense Ovarian Cancer Research Program.
ARIEL2 is funded by Clovis Oncology. Methylation analyses were supported by the Stand Up To Cancer – Ovarian Cancer Research Fund Alliance – National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15 to ES). Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C.
Medical writing and editorial support was funded by Clovis Oncology, and provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications.
CITE THIS ARTICLE:
Elizabeth M. Swisher, MD. Characterization of patients with ovarian carcinoma who respond to the PARP inhibitor rucaparib. Doctors Lounge. Available at: https://www.doctorslounge.com/index.php/articles/page/71342. Accessed September 23 2017.
- Rubraca (rucaparib) tablets [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2016.
- 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. 2017;18(1):75-87.
- Swisher EM, Harrell MI, Lin K, et al. BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1 2017; https://www.sgo.org/education/annual-meeting-on-womens-cancer/annual-meeting-abstracts-2/. Accessed March 30, 2017.
- Konecny GE, Oza AM, Tinker AV, et al. Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: Integrated summary of efficacy and safety from the phase II study ARIEL2. 2017; https://www.sgo.org/education/annual-meeting-on-womens-cancer/annual-meeting-abstracts-2/. Accessed March 30, 2017.
- Norquist B, Wurz KA, Pennil CC, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29(22):3008-3015.