PARP Inhibitors gBRCA1/2-Mutated Pancreatic Cancer


John Marshall, MD: Paul, there’s been interest from CNN and New England Journal of Medicine, as well as a plenary session around targeted therapies in pancreatic cancer. What’s all the buzz?

Paul Oberstein, MD: This is truly exciting if Shubham is a little disappointed.

Shubham Pant, MD: Some disappointment.

Paul Oberstein, MD: This was an ambitious study that—I have to admit—at the beginning, I thought was overly ambitious, and they pulled it off. They looked at patients with metastatic pancreatic cancer, who were then screened for germline mutation in BRCA1 or BRCA2. They looked at over 3000 patients internationally, and identified around 150 who had a germline mutation, so around 7% or 8%.

John Marshall, MD: I just want to make sure and reclarify, because we were talking earlier about HRD [homologous recombination deficiency] and other targets. This was just BRCA1 and BRCA2 germline mutation.

Paul Oberstein, MD: This was just BRCA1 and BRCA2.

John Marshall, MD: Not the somatic stuff?

Paul Oberstein, MD: One tube of blood. It shows you the power. If you’re doing blood instead of tumor biopsies, you can get 3000. If you’re doing biopsies, we’re still struggling to get a few hundred.

John Marshall, MD: Very good point.

Paul Oberstein, MD: They did a great job of collecting this, testing it, getting the results back quickly. Patients had to then remain on first-line chemotherapy for at least 4 months and not progress. If they met that criterion and they had this germline blood mutation of BRCA1 or BRCA2, they were eligible to be randomized to either get an oral PARP inhibitor, olaparib, or an oral placebo. It was a blinded study. What the study showed was that those who got the PARP inhibitor had around a doubling of the time until their tumor recurred, compared with those who got essentially nothing, which I think was validation of this concept that a PARP inhibitor in the patient with the right selection—which is a very small population—can provide benefit.

John Marshall, MD: Ed, what’s this do to your thinking about—it’s a controversial trial design and a controversial result.

Edward Kim, MD: This just reinforces what we talked about in the very beginning. We need to test all patients’ germline and to be able to use it.

John Marshall, MD: Because you’ll play this therapy option for all these patients?

Edward Kim, MD: One of the things you mentioned was the improvement in progression-free survival. That doubled that time, but at the end of the day, I think we also very much care about how long our patients survive, meaning the overall survival. That did not show a difference between those 2 arms of being on a placebo and being on a PARP inhibitor. I think we have to think very carefully about how to interpret that.

John Marshall, MD: We’ll let him have his word in a minute.

Edward Kim, MD: For me, I’m not sure it changes what I would practice right now, but it gives me some pause to think about whether this is more evidence that we need to have this information and be able to actually apply this. We don’t know.

John Marshall, MD: Back to our maintenance discussion, right? We were talking about breaks versus maintenance. If you had a BRCA patient, in that 5% or so of patients, this would be your capecitabine. You would use this instead. Is that fair?

Edward Kim, MD: I think that’s fair. There is toxicity. I don’t think we can overlook that, but there is some toxicity with PARP inhibitors—nausea, GI [gastrointestinal] symptoms, and fatigue.

Allyson Ocean, MD: It’s a lot better than FOLFIRINOX [folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin].

Edward Kim, MD: It’s definitely better than FOLFIRINOX.

John Marshall, MD: It’s not voodoo target, it’s chemotherapy-like. It’s DNA damaging.

Transcript Edited for Clarity

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