Charles Drake, MD, PhD
Following in the steps of ovarian cancer, PARP inhibitors have begun to show promise in metastatic castration-resistant prostate cancer. Olaparib (Lynparza), in particular, has demonstrated high response rates in patients with DNA-repair defects.
, Drake shared insight on the current status of both PARP inhibitors and immunotherapy in prostate cancer, emphasizing that immunotherapy is still very much a player in the prostate cancer field, with ongoing trials exploring checkpoint inhibitors.
OncLive: What is the excitement with PARP inhibitors in prostate cancer?
The paper that Dr Johann de Bono's group published in the New England Journal of Medicine a couple of years ago suggested that patients with mutations and DNA damage-repair genes demonstrated high responses to PARP inhibitors. The responses were nice and very meaningful, and some of them persisted for a very long time. That is a very important clinical finding.
There was also a paper by the Seattle Cancer Care Alliance by Dr Colin C. Pritchard and Dr Peter Nelson's group where they showed that about 12% of men with advanced metastatic prostate cancer had germline defects in these DNA mismatch-repair genes. These were things like BRCA1/2, and that was fascinating because that meant with a simple genetic test—a germline genetic test—you could identify potential patients. If you add up the germline defects and the new or acquired defects, it is probably high—in the 20% to 30% range. That is important because that means there is a very meaningful treatment option for about one-quarter of men with prostate cancer.
What is your advice for community oncologists and urologists approaching PARP inhibitors in this patient population?
Right now, it is in flux. There are large randomized trials—I believe there are 3 of them—that are testing PARP inhibitors in selected patients. There are a lot of unknowns right now. I always ask the experts, “What is the best way to screen patients for PARP inhibitors?” It turns out that the clinical trials are using different screening methods. To be honest, right now, we do not know the best way to screen these patients. The other thing is that not all mutations are created equally. Some of the mutations render the tumors sensitive to PARP inhibition, and others do not. These are data that will come out from the randomized phase III trials.
It is a very interesting time right now. You could easily do genomic testing to predict for PARP inhibitor response, and you could also test the tumor by sequencing. Do you need to do both? Who are the best patients to do it in? What are the chances that the drug works? Here is what I can tell you that is interesting: if you talk to oncologists in academia as well as those in private practice, you'll find out that many of them have tried PARP inhibitors.
The simplest test to do is basically a germline DNA test. It is available from a few different companies but one that is used frequently is from a company called Color. The patient swabs their cheek, the test performs germline sequencing on 30 genes, and we get the data back about 2 or 3 weeks later. That catches about half of the patients. It is fascinating clinically, because if the patient cannot get on a trial or does not have access to a trial, how do you know when to use this drug? [Do we give it] before or after chemotherapy? Certainly, [we should give it] after second-line hormonal therapy, such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi). We don't know if we should do chemotherapy first; it is a very evolving field in terms of where and when these drugs are going to be used. There will be a lot of clarity when these trials come out, but right now it is very much a field in flux.
What are your thoughts on this shift toward precision medicine?
We have to be a little careful with the term "precision medicine" because what is happening now is very similar to what happened with targeted therapy and immunotherapy. In the early days, people would present beautiful, anecdotal responses to mutations that they found. For immunotherapy, many early trials of vaccines showed that when you did careful randomized trials, the clinical benefit of these approaches was maybe not as great as we thought.
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