Abstract
Pancreatic cancer is the third most common cause of cancer death in the United States and eleventh worldwide. The majority of patients present with advanced disease with five-year overall survival of less than 10%. Traditional chemotherapy has been the mainstay treatment for years, with limited improvement in survival. Relative success has been achieved with agents targeting the DNA damage repair (DDR) mechanisms with poly adenosine diphosphate-ribose polymerase (PARP) inhibitors. The initial benefit was observed in patients with germline breast cancer-associated (BRCA) mutations. Multiple trials are now underway exploring PARP inhibitors in other DDR mutations such as the ataxia-telangiectasia mutated (ATM) gene and the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (familial atypical multiple mole and melanoma syndrome), mismatch repair genes (Lynch syndrome), and others. PARP inhibitors are being evaluated as a single agent or combination chemotherapy, immunotherapy, and maintenance after chemotherapy. Here, we review current clinical trials targeting various DDR mutations and treatment strategies.
Highlights
BackgroundPancreatic cancer comprises 3.2% of all new cancer cases in North America and 3% of cases worldwide
This review focuses mainly on the clinical trials of several poly adenosine diphosphate-ribose polymerase (PARP) inhibitors to date and those currently underway to assess the efficacy of PARP inhibitors in the treatment of pancreatic cancer (Table 2) [30,31,32]
Pancreatic cancer has an abysmal prognosis and chemotherapy has been the mainstay of treatment with limited improvement in survival
Summary
Pancreatic cancer comprises 3.2% of all new cancer cases in North America and 3% of cases worldwide. NCT03637491 [56] is an ongoing phase 1b/II study evaluating the safety and efficacy of avelumab, binimetinib, and talazoparib combination in patients with locally advanced or metastatic Ras-mutant solid tumors including pancreatic cancer patients. Niraparib as combination therapy (with immunotherapy): Parpvax (NCT03404960) is a phase Ib/II study of niraparib plus ipilimumab (phase 2), niraparib plus nivolumab (phase 1) evaluating the safety, effectiveness, and antitumor activity (preventing tumor growth) in patients with advanced pancreatic cancer whose disease has not progressed on platinum-based therapy for at least 16 weeks [59]. PFS: progression-free survival; OS: overall survival; ORR: objective response rate;BRCA: breast cancer-associated ; ATM: ataxia-telangiectasia mutated; PALB2: partner and localizer of BRCA2; HRD: homologous recombination deficiency
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