Isaacson, Jeffrey D.

Abstract A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. Significance: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity. This article is highlighted in the In This Issue feature, p. 151

Abstract Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA mutation. Though less well characterized to date, somatic BRCA mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

Abstract Background: PARP inhibitors are thought to be effective therapy for cancers with homologous recombination (HR) deficiency, best shown to date in patients (pts) with a germline BRCA (gBRCA) mutation. The Cancer Genome Atlas (TCGA) estimated ∼ 50% of high-grade serous ovarian carcinoma (OC) pts have an HR defect (HRD) due to a BRCA mutation (germline or somatic), other HR gene mutation, or another mechanism, e.g., BRCA1 promoter methylation. A randomized maintenance trial of olaparib in recurrent OC demonstrated a clinical benefit in both gBRCA-mutated and gBRCA-wild-type pts. Currently, the best molecular predictors of PARPi response (other than a BRCA mutation) are not known. Platinum sensitivity, often used as a surrogate predictive indicator for PARPi response, is inadequate. A better technique, such as molecular analysis of tumor tissue, could be a superior method for selection of pts for PARPi therapy. Methods: The rucaparib development plan in OC employs a unique strategy of conducting the key trials in parallel, allowing the Phase 2 (ARIEL2) to complete first so that a molecular HRD signature, associated with sub-groups most likely to benefit, can be prospectively applied to the final analysis of the Phase 3 pivotal trial (ARIEL3). ARIEL2 is an ongoing, single-arm, open-label biomarker study designed to refine the molecular signature associated with a response to rucaparib. Eligible pts (n=180) have relapsed, platinum-sensitive, high-grade OC and measurable disease. All pts undergo a pre-dose biopsy and provide archival tumor tissue. Tumor tissue HR status is assessed using Foundation Medicine's next generation sequencing (NGS) platform and University of Washington's BROCA-HR panel, with the current HRD algorithm developed using in vitro/in vivo and TCGA (and similar) bioinformatic data. The key efficacy analyses to be correlated with tumor HR status are response by RECIST v1.1, GCIG-defined CA-125 response, and PFS. The number of gBRCA pts is limited to maximize non-gBRCA response predictors. Exploratory biomarkers include assessment of tissue NHEJ competency (candidate predictive biomarker) and circulating tumor DNA (candidate efficacy surrogate). The optimized algorithm will then be tested prospectively in ARIEL3 (n=540), an international, randomized (2:1), double-blind, placebo-controlled maintenance trial in platinum-sensitive OC in remission after platinum-based therapy. The primary endpoint of ARIEL3 is PFS in molecularly-defined HRD subgroups as determined by NGS analysis of archival tumor tissue using the optimized algorithm, refined (as required) through ARIEL2.Conclusion: This pair of clinical trials seeks to determine prospectively the appropriate population, among all women with platinum-sensitive OC, who derive a meaningful benefit from PARPi treatment in the maintenance setting. Citation Format: Elizabeth Swisher, Iain McNeish, Robert L. Coleman, James D. Brenton, Scott H. Kaufmann, Andrew Allen, Mitch Raponi, Heidi Giordano, Lara Maloney, Jeffrey Isaacson, Jonathan A. Ledermann. Prospective molecular identification of ovarian cancer patients benefiting from PARP inhibitor (PARPi, rucaparib) maintenance therapy - reaching beyond germline BRCA mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT339. doi:10.1158/1538-7445.AM2014-CT339