PARP Inhibitors in Pancreatic Cancer

Transcript:Tanios Bekaii-Saab, MD: There are a number of agents that continue to be pursued in pancreas cancer. We had a lot of studies that actually suggested that the number of targeted approaches did not pan out into positive results. There’s one area that seems to be very interesting, that is continuing through drug development, and that’s patients with proven BRCA2, BRCA1, or PALB2 mutation. And, frankly, whether it’s germ line or somatic, meaning it’s present in the tumor only or it’s present in the genetics of the patient, it does not matter for the level of responsiveness that we see with platinums or with emerging PARP inhibitors. Specifically, there are two PARP inhibitors that hold a lot of promise in pancreas cancer: olaparib and rucaparib. But, there may be others that are also third generation. The one that seems to be the least interesting, unfortunately, is an agent called veliparib, or ABT-888, which seems to be less potent and holds a little bit less promise, but still is worthy of exploring further.

The question is, what percent of patients would be BRCA2-, BRCA1-positive or PALB2-positive? This would be about 10% to 12% of patients that have either germ-line or somatic mutations, and 10% is a sizable number. In addition to that, there is this whole concept of what we call BRCAness. They’re not quite BRCA, but there are a lot of abnormalities that induce genomic instability that could resemble these mutations or sensitivity to these agents that essentially are active in the presence of these mutations. This is another 12% to 13% of the patients, although, again, it’s mostly established in ovarian and breast, not yet in pancreas, but this is work in evolution. So, you may end up with about 20% to 25% of all your patients that have either BRCA or BRCAness. What drives response in those agents—so, we talked about the PARP inhibitors—the other group of agents are actually the platinums—cisplatin, oxaliplatin. Then, the next logical question is, should we take oxaliplatin and PARP inhibitors and put them together? So, a study is being conducted with cisplatin, gemcitabine, and one of the PARP inhibitors. Although, if you look back at the preclinical literature, it suggests that perhaps it is not optimal to combine a platinum with a PARP inhibitor in this group of patients. It makes more sense to combine a topoisomerase inhibitor, like irinotecan or MM-398, with a PARP inhibitor to induce a better response in those patients.

When you think about this group of patients, with what we have as standard of care today, FOLFIRINOX will probably make more sense, because of the presence of the platinum. And what would make sense, in terms of drug development, is to do a 5-FU/MM-398, or 5-FU/irinotecan preferred with 5-FU/MM-398 with a PARP inhibitor—again, olaparib, or rucaparib, or some of the other emerging PARP inhibitors.

When we look at the patients with BRCA mutations, especially, right now, when we’re looking at the clinical landscape where you have FOLFIRINOX as one option—although gemcitabine/cisplatin can be another option—after a few months of therapy, patients get tired of the chemotherapy. And so, the question is, can you maintain those patients on a single-agent PARP inhibitor, for example, once you actually control the disease or shrink it to a level? And the answer is, we don’t know, we need to study that. And a study is being conducted with olaparib versus no treatment, versus placebo. That study is looking at maintenance strategy following a platinum derived chemotherapy, so FOLFIRINOX with gem/cisplatin or even carboplatin-paclitaxel, in some instance. This study is currently accruing. It’s only selecting for patients, though, with germ-line mutations, not somatic mutations. So, that’s only targeting 2% to 3% of the patient population. But, these strategies are worthy of exploring, because, frankly, patients get tired from going through chemotherapy after 6 months. If we have a strategy, especially in that subgroup of patients where we can maintain that response without adding the toxicities, it would be a great place for PARP inhibitors to be looked at.

Transcript Edited for Clarity