PARP Inhibitors Hold Promise in Pancreas Cancer

Eileen O'Reilly, MD, MB BCh


June 17, 2013

In This Article

Will PARP Inhibitors Prove Active?

The treatment implications for patients with a BRCA mutation are that certain drugs -- for example, the platinum agents and topoisomerase-1 inhibitors and standard cytotoxics -- may have enhanced benefit for this patient population. Experimental drugs such as the poly ADP-ribose polymerase (PARP) inhibitors may also have an increased activity in BRCA-mutated pancreas cancer. This is related to the inhibition of DNA repair by platinum agents, topoisomerase inhibitors, and PARP inhibitors, in that cells may not be effectively able to repair initially single-stranded and cumulatively double-stranded DNA breaks and can have a heightened susceptibility in tumor cells over normal tissue. That is the important concept -- synthetic lethality -- and a reason why this may represent a targeted opportunity for treatment of a certain subset of patients with pancreas adenocarcinoma.

At Memorial Sloan-Kettering, in collaboration with the National Cancer Institute and with collaborations with Israel and other sites in the United States and Canada, we are conducting several trials that are designed to elucidate the activity of platinum drugs in this subpopulation of BRCA and PALB2 mutated pancreas cancer by combining PARP inhibitors with the cytotoxic backbone of cisplatinum and gemcitabine.[1] Currently, that study is in a dose-finalization stage, and our plan is to randomly assign these patients to the cytotoxic cisplatinum and gemcitabine backbone, plus or minus veliparib, the PARP inhibitor. The purpose is to more fully understand whether it is the platinum agents or the PARP inhibitor, or both, that add to improved activity for this patient population.

Similarly, we have a second- or third-line trial looking at single-agent, higher dosing of the PARP inhibitor in patients with previously treated BRCA- or PALB2-mutated pancreas cancer. These exciting trials have been under way for the past year and are accruing quite readily. We have some interesting early activity, so there will be more to come on this topic.

At this meeting, we heard more data[2] on the activity of PARP inhibitors in a broader study of patients with a variety of BRCA-mutated malignancies, mostly breast and ovary cancer, but also a subset of patients with pancreas cancer. Those data further support the role for this treatment strategy in this disease.


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