Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation

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 germ-line; 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.

Update on PARP inhibitor therapy for solid tumors

“…RUCAPANC trial reported 32% ORR among patients with APC harboring BRCA1/BRCA2 mutation. 57 Veliparib on the other hand has not shown any benefit among this patient population. 58,59 Phase III POLO trial 60 APC patients with germline BRCA1/ BRCA2 mutated APC were treated with olaparib 300 mg twice daily or placebo after ≥16 weeks of platinum-based regimen.…”

Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

“…Our results support broader panel testing as a way to identify unexpected high-penetrant PVs in eoRC patients, when there is a personal or family history of additional cancers (especially an HBOCsyndrome cancer). This is important because identification of a BRCA PV can potentially change medical management; for instance, PARP inhibitor therapy is effective in tumors with BRCA PVs, including non-breast tumors (24,25). Also, screening and prevention of HBOCsyndrome cancers will be increased significantly in the proband and family members found to have the same PV.…”

Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response

“…Olaparib is an oral PARP inhibitor that, in the setting of BRCA‐ deficient cells, functions as a cytotoxic agent by blocking base excision repair, which eventually leads to double‐strand breaks, subsequent DNA replication fork stalling, and cell death . In certain cancer types with high mutation rates in genes involved with homologous recombination components, such as high‐grade serous ovarian, triple‐negative breast, metastatic prostate, or pancreatic tumors, PARP inhibitors have proven to be effective treatment strategies .…”

“…Olaparib is an oral PARP inhibitor that, in the setting of BRCAdeficient cells, functions as a cytotoxic agent by blocking base excision repair, which eventually leads to double-strand breaks, subsequent DNA replication fork stalling, and cell death [14]. In certain cancer types with high mutation rates in genes involved with homologous recombination components, such as highgrade serous ovarian, triple-negative breast, metastatic prostate, or pancreatic tumors, PARP inhibitors have proven to be effective treatment strategies [15][16][17][18]. Emerging evidence suggests that PARP inhibitors may also be a novel therapeutic option for patients with GBM, given the upregulation of DNA repair genes like ATM, ATR, CHK1, and PARP as well as the high capacity for DNA repair in glioma stem cells [19].…”