PARP Inhibitors in Prostate Cancer - Episode 2
An expert oncologist discusses the biomarker testing targets in metastatic prostate cancer.
Matthew Fowler: With biomarker testing, what targets are you specifically looking for? Which of these have therapeutic implications?
Oliver Sartor, MD: Several are covered by the FDA as having approved therapies. One would be the homologous recombination repair genes. These are the well-known BRCA1 and BRCA2 but also potentially other genes, such as ATM, CHEK2, PALB2. There’s a whole list of these that are part of the olaparib FDA approval; that’s easily referenceable. I can’t remember all 14 genes, but I don’t have to. I can look it up when I need to. For the rucaparib-accelerated approval, those are both for castration-resistant disease. We’re not talking about the initial diagnosis—that’s a BRCA1 and a BRCA2 story, which is a little different for the rucaparib predictive biomarkers, as opposed to the olaparib FDA approval.
Of course, we have mismatch repair genes; there are ways you can look at this. In nongenomic manners, you can look at immunohistochemistry for things like MSH2 and MSH6, where for the classic mismatch repair genes you’ll get loss in protein staining. You can also pick it up genomically; it’s nice to do both. We have another parameter called MSI [microsatellite instability], which can be looked at it in a very specific genomic type test. It’s amplifying the little CAG repeats, the little triplet repeats that you can see in tumors. They have instability when there’s mismatch repair alterations.
We can also look at tumor mutational burden [TMB], which is important. Let’s draw that together. Mismatch repair deficiency, MSI-high, and high tumor mutational burden are all indications for the future use of pembrolizumab. Not initially in the up-front setting, but for pembrolizumab very specifically. I named the drug by name because it’s not all PD-1 inhibitors. This is FDA approved in a tumor-agnostic fashion. There are other things out there I’m potentially looking for, but that’s in a more experimental sense. I’ll stop right there and say that homologous recombination repair, mismatch repair, MSI-high, and TMB—put that together. Those are the predictive biomarkers that are FDA approved today.
Matthew Fowler: What are some of the challenges or barriers to getting biomarker testing?
Oliver Sartor, MD: It turns out, for the germline, there are very few barriers today. We generally do this as part of our routine. I know that there’s potentially some controversy with the way we approach it, because I don’t refer to a genetic counselor up front. We tried that model, and by the way, others have as well. Hospitals like Royal Marsden [in London, England] have also managed to do it without the genetic counselor being involved from day 1. We go through the pros and cons, and I’m there to answer any questions. Yes, there are some issues related to germline. Not on the medical front, but you can be discriminated for life insurance, you can be discriminated for various employee insurance, not for medical insurance. It turns out that discrimination for life insurance can play an important role for certain individuals; that can be a challenge for the germline side.
On the somatic side, the real test is going to be reimbursement issues that arise. Not everyone is going to have insurance that will embrace the NGS [next-generation sequencing] approach toward tissue. Sometimes we must fight that battle a little. There’s also the potential challenge that tissue can be very scarce, or it’s difficult to obtain. It’s not uncommon that we may have a patient who was seen and diagnosed in a community urology clinic 7 years ago, and then they show up to me with metastatic disease. If we’re trying to get archival tissue, then we must chase that community hospital sample from 7 years ago. That could be a substantial issue. We don’t have any problems with circulating tumor DNA, so then I move a little more toward the circulating tumor DNA if I have trouble with the somatic tissue, getting the tissue. Sometimes you just can’t get tissue at all. Sometimes you get tissue and there are quality control problems. If we look at the large olaparib study called PROfound, it turns out that about 30% of the patients who had had a sample submitted did not have a result because of quality control issues with the DNA of the tissue. The variety of potentially problematic issues whenever you’re starting to try to get a piece of tissue from somebody diagnosed with prostate cancer can run all the way from a tissue availability to quality and reimbursement issues. All those have to be dealt with.
Transcript edited for clarity.