Abstract
Survival rates for pancreatic cancer remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops. Tumors deficient in deoxyribonucleic acid (DNA) damage repair mechanisms such as BRCA mutants show better responses to platinum based agents, however, such tumors can utilize the poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) pathway as a salvage mechanism. Therefore, inhibition of PARP pathway could lead to tumor destruction and synthetic lethality in presence of BRCA mutation. Various PARP inhibitors have been approved for treatment of patients with germline or somatic BRCA mutant breast and ovarian cancer. This provides basis of using PARP inhibitors in patients with pancreatic cancer that harbor BRCA mutation. A recent phase III Pancreas Cancer Olaparib Ongoing (POLO) study showed impressive results with near doubling of progression free survival compared to placebo (7.4 vs 3.8 months). These results highlight the importance of germline testing for all patients with pancreatic cancer and inclusion of additional deficiencies in homologous recombination repair (ATM and PALB2) including BRCA variants of uncertain significance should be further explored.
Highlights
Survival rates for pancreatic cancer remain dismal
Genes involved in deoxyribonucleic acid (DNA) damage repair (DDR) may contribute to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and deficiency in DDR mechanism leads to an increased risk of cancer
It is known that poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) 1/2 detect DNA damage and promote its repair.[8]
Summary
Phase I studies were conducted after having demonstrated synthetic lethality with PARP inhibitors using in vitro models. In a study of 60 patients, 22(37%) of whom were known carriers of a BRCA 1 or BRCA 2 mutation, received olaparib at escalating doses. Dosing of olaparib was started at 10 mg daily for two of every three weeks, and was doubled every cycle of treatment, if tolerated. This trial demonstrated that the maximum tolerated dose of olaparib to be 400 mg twice daily. 12 of 19 (63%) patients had clinical benefit defined as radiologic response (complete or partial response) based on response evaluation criteria in solid tumors (RECIST), tumor-marker responses defined as a decline in the tumor-marker level of more than 50% that was sustained for at least 4-weeks, or stable disease for a period of 4-months or more.[9] 23 patients with BRCA mutation were treated and 19 patients were evaluated for response. 12 of 19 (63%) patients had clinical benefit defined as radiologic response (complete or partial response) based on response evaluation criteria in solid tumors (RECIST), tumor-marker responses defined as a decline in the tumor-marker level of more than 50% that was sustained for at least 4-weeks, or stable disease for a period of 4-months or more.[9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
