Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation

Shroff, R. T. et al. (2018) Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precision Oncology, 2(1), (doi: 10.1200/po.17.00316) (PMID:30051098) (PMCID:PMC6057747)

Abstract

Purpose: Pancreatic cancer has a poor prognosis and limited treatment options. Approximately 9% of pancreatic cancers harbor a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation. Because poly (ADP-ribose) polymerase inhibitors have significant activity in BRCA1/2-mutant ovarian and breast cancers, RUCAPANC investigated the efficacy and safety of rucaparib in BRCA1/2-mutant pancreatic cancer. Patients and Methods: RUCAPANC enrolled patients with measurable locally advanced/metastatic pancreatic cancer who had received one to two prior chemotherapy regimens. Patients received oral rucaparib (600 mg twice daily) until disease progression. The primary end point was objective response rate. Results: Nineteen patients were enrolled. Sixteen of 19 BRCA1/2 mutations were germline; three were somatic. Patients had received a median of two prior chemotherapy regimens. Four patients achieved a response; two partial responses and one complete response (CR) were confirmed (objective response rate, 15.8%; 3 of 19), with an additional CR unconfirmed. The disease control rate (CR, partial response, or stable disease for ≥ 12 weeks) was 31.6% (6 of 19) in all patients and 44.4% (4 of 9) in those who had received one prior chemotherapy regimen. As prespecified in the protocol, enrollment was stopped because of an insufficient response rate among the first 15 patients. Treatment-emergent adverse events included nausea (63.2%) and anemia (47.4%). Grade ≥ 3 adverse events included anemia (31.6%), fatigue (15.8%), and ascites (15.8%). Secondary resistance mutations were detected in circulating free tumor DNA in two patients with a germline BRCA2 mutation. These mutations are predicted to lead to the reversion of a somatic—not germline—mutation. Conclusion: Rucaparib provided clinical benefit to patients with advanced pancreatic cancer and a BRCA1/2 mutation, and demonstrated an acceptable safety profile. Additional trials of rucaparib in this population are warranted.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Biankin, Professor Andrew
• Authors: Shroff, R. T., Hendifar, A., McWilliams, R. R., Geva, R., Epelbaum, R., Rolfe, L., Goble, S., Lin, K. K., Biankin, A. V., Giordano, H., Vonderheide, R. H., and Domchek, S. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: JCO Precision Oncology
• Publisher: American Society of Clinical Oncology (ASCO)
• ISSN: 2473-4284
• ISSN (Online): JCO Precision Oncology
• Published Online: 16 May 2018