Select Topic:
Browse by Series:

Checkpoint Inhibitor Therapy in Prostate Cancer

Insights From: Daniel Petrylak, MD, Yale University; Nicholas Vogelzang, MD, Comprehensive Cancer Center
Published: Friday, Apr 03, 2020



Transcript:

Nicholas Vogelzang, MD: In the world of checkpoint inhibitors, do we have any data yet that monotherapy with checkpoint inhibitor has a role in prostate cancer?

Daniel Petrylak, MD: Well, we all should be testing our patients for microsatellite instability. That is an FDA-approved indication for pembrolizumab. About 3% of prostate cancer patients do have that. In that paper that I cited before from Memorial Sloan Kettering Cancer Center about microsatellite instability there was a section on those patients who were treated. About half of those patients responded to a checkpoint inhibitor. I think that can make a significant difference in our patients’ outcomes.

Charles Ryan, MD, has got a case that I think is very interesting about a patient who had a complete response to a checkpoint inhibitor who was microsatellite unstable. Now he doesn’t know what to do as to far as whether he should continue treatment, and whether this patient should stop hormone therapy.

Nicholas Vogelzang, MD: One of my friends, David Shaffer, MD, in Albany, has a similar case where he gave atezolizumab in an earlier trial, that was an atezolizumab/enzalutamide trial, which you may want to comment on. And the patient is in a 5-year remission. There’s no clear genetic reason for him to be in this remission. They’ve biopsied him several times and there’s been no obvious, there’s no Lynch syndrome, there are no DNA repair issues. Occasionally there are these unusual responses to checkpoint inhibitors.

Daniel Petrylak, MD: I think we underestimate. We think about a drug’s mechanism as being monolithic. The kinase inhibitors inhibit multiple kinases. Abiraterone, as we talked about before, can downregulate DNA repair. Enzalutamide, a couple of years ago, surprisingly has an immune-modulatory effect.
And Julie Graff, MD, from Oregon has actually exploited that particular observation, looking at combinations of pembrolizumab plus enzalutamide, and showing that there is significant activity between the 2.

Now there was a randomized trial of atezolizumab with enzalutamide. Unfortunately, it’s only been reported in press release form at this point; it was negative. Again it emphasizes the fact that we cannot treat all-comers. We have to understand the biology and tailor our treatments for individual patients.

Nicholas Vogelzang, MD: As I understand it, Merck & Co, Inc is looking at a number of combination trials. I remember there’s at least docetaxel with or without PEMBRO [pembrolizumab].

Daniel Petrylak, MD: Right, exactly.

Nicholas Vogelzang, MD: What are the other ones that are going?

Daniel Petrylak, MD: I think there are 4 interesting trials that Merck is doing right now. The docetaxel, plus or minus pembrolizumab, which I’m one of the PIs [principal investigators] on, so I’ve got to disclose that. The enzalutamide plus or minus pembrolizumab. There’s an olaparib plus or minus pembrolizumab as well. And the other interesting trial that is about to open, which I am very excited about, is pembrolizumab plus enzalutamide, and androgen blockade, up front.

Nicholas Vogelzang, MD: In hormone sensitive.

Daniel Petrylak, MD: Yes, in hormone-sensitive disease. The question is, is the immune milieu different in hormone sensitive versus castrate resistant? A lot of people do think that you have a different immune response in that particular situation. Certainly, when you’re inducing hormone therapy, you’re causing a large release of antigens from the prostate cancer cell apoptosis, and perhaps that’s the right time to administer immune therapy because then you can use that system to clean up the cellular debris. It’s going to be an interesting trial to be coming out.

Nicholas Vogelzang, MD: Well these are big trials. MERCK has put a large amount of effort into designing and conducting these. There are some negatives. One, for example, is that it’s placebo controlled. The enzalutamide trial, there are patients getting placebo pembrolizumab. We’ll see if the patients accept those kind of restrictions.

Daniel Petrylak, MD: Talk about the full gambit of these trials, nivolumab is also being looked at in a randomized trial, nivolumab plus DOCE [docetaxel] versus docetaxel alone. There are a number of different trials that out there looking at immune checkpoints.

The interesting thing about both nivolumab plus docetaxel as well as pembrolizumab plus docetaxel, is that radiographic progression-free survival does seem to be a little bit better than what’s been reported in the past. And remember, these patients are supposed to have abiraterone. And the survival of docetaxel from some reports is a little bit less in those patients. Perhaps, you know, it’s hard to compare this because they are different eras.

Nicholas Vogelzang, MD: Yes, very different eras.

Daniel Petrylak, MD: I think there are very interesting data that are going to be generated from this.

Nicholas Vogelzang, MD: Well, your initial work with docetaxel, which really laid the foundation for docetaxel in metastatic disease, has now spawned a whole series of docetaxel-plus trials.

Daniel Petrylak, MD: Right.

Nicholas Vogelzang, MD: I think it’s fair to say that those first-generation trials didn’t enhance docetaxel. What’s your perspective? Are we barking up the same tree again, or is this different?

Daniel Petrylak, MD: I think that’s a great question. I think it’s a little bit different. When those trials were all designed after the SWOG study and after the TAX-327 trial, I think everybody was looking to get into the game of having their drug married to docetaxel and then moving forward. We understood the biology to some degree, but we didn’t understand it that well. Now I think we’re really understanding the biology better; docetaxel is still a great drug for this disease. It’s hard to knock it off as a comparator arm. You’ve got to move the bar up much higher to see it.

Nicholas Vogelzang, MD: If you’re a betting man, are you going to bet that the immune checkpoints are going to add something to docetaxel?

Daniel Petrylak, MD: I’ll bet on that. But you know the other line too is that 1 in 20 trials are going to be positive based upon statistics. We’ve got to have 1 positive study. But no, I think there’s good reason to be optimistic with these.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Nicholas Vogelzang, MD: In the world of checkpoint inhibitors, do we have any data yet that monotherapy with checkpoint inhibitor has a role in prostate cancer?

Daniel Petrylak, MD: Well, we all should be testing our patients for microsatellite instability. That is an FDA-approved indication for pembrolizumab. About 3% of prostate cancer patients do have that. In that paper that I cited before from Memorial Sloan Kettering Cancer Center about microsatellite instability there was a section on those patients who were treated. About half of those patients responded to a checkpoint inhibitor. I think that can make a significant difference in our patients’ outcomes.

Charles Ryan, MD, has got a case that I think is very interesting about a patient who had a complete response to a checkpoint inhibitor who was microsatellite unstable. Now he doesn’t know what to do as to far as whether he should continue treatment, and whether this patient should stop hormone therapy.

Nicholas Vogelzang, MD: One of my friends, David Shaffer, MD, in Albany, has a similar case where he gave atezolizumab in an earlier trial, that was an atezolizumab/enzalutamide trial, which you may want to comment on. And the patient is in a 5-year remission. There’s no clear genetic reason for him to be in this remission. They’ve biopsied him several times and there’s been no obvious, there’s no Lynch syndrome, there are no DNA repair issues. Occasionally there are these unusual responses to checkpoint inhibitors.

Daniel Petrylak, MD: I think we underestimate. We think about a drug’s mechanism as being monolithic. The kinase inhibitors inhibit multiple kinases. Abiraterone, as we talked about before, can downregulate DNA repair. Enzalutamide, a couple of years ago, surprisingly has an immune-modulatory effect.
And Julie Graff, MD, from Oregon has actually exploited that particular observation, looking at combinations of pembrolizumab plus enzalutamide, and showing that there is significant activity between the 2.

Now there was a randomized trial of atezolizumab with enzalutamide. Unfortunately, it’s only been reported in press release form at this point; it was negative. Again it emphasizes the fact that we cannot treat all-comers. We have to understand the biology and tailor our treatments for individual patients.

Nicholas Vogelzang, MD: As I understand it, Merck & Co, Inc is looking at a number of combination trials. I remember there’s at least docetaxel with or without PEMBRO [pembrolizumab].

Daniel Petrylak, MD: Right, exactly.

Nicholas Vogelzang, MD: What are the other ones that are going?

Daniel Petrylak, MD: I think there are 4 interesting trials that Merck is doing right now. The docetaxel, plus or minus pembrolizumab, which I’m one of the PIs [principal investigators] on, so I’ve got to disclose that. The enzalutamide plus or minus pembrolizumab. There’s an olaparib plus or minus pembrolizumab as well. And the other interesting trial that is about to open, which I am very excited about, is pembrolizumab plus enzalutamide, and androgen blockade, up front.

Nicholas Vogelzang, MD: In hormone sensitive.

Daniel Petrylak, MD: Yes, in hormone-sensitive disease. The question is, is the immune milieu different in hormone sensitive versus castrate resistant? A lot of people do think that you have a different immune response in that particular situation. Certainly, when you’re inducing hormone therapy, you’re causing a large release of antigens from the prostate cancer cell apoptosis, and perhaps that’s the right time to administer immune therapy because then you can use that system to clean up the cellular debris. It’s going to be an interesting trial to be coming out.

Nicholas Vogelzang, MD: Well these are big trials. MERCK has put a large amount of effort into designing and conducting these. There are some negatives. One, for example, is that it’s placebo controlled. The enzalutamide trial, there are patients getting placebo pembrolizumab. We’ll see if the patients accept those kind of restrictions.

Daniel Petrylak, MD: Talk about the full gambit of these trials, nivolumab is also being looked at in a randomized trial, nivolumab plus DOCE [docetaxel] versus docetaxel alone. There are a number of different trials that out there looking at immune checkpoints.

The interesting thing about both nivolumab plus docetaxel as well as pembrolizumab plus docetaxel, is that radiographic progression-free survival does seem to be a little bit better than what’s been reported in the past. And remember, these patients are supposed to have abiraterone. And the survival of docetaxel from some reports is a little bit less in those patients. Perhaps, you know, it’s hard to compare this because they are different eras.

Nicholas Vogelzang, MD: Yes, very different eras.

Daniel Petrylak, MD: I think there are very interesting data that are going to be generated from this.

Nicholas Vogelzang, MD: Well, your initial work with docetaxel, which really laid the foundation for docetaxel in metastatic disease, has now spawned a whole series of docetaxel-plus trials.

Daniel Petrylak, MD: Right.

Nicholas Vogelzang, MD: I think it’s fair to say that those first-generation trials didn’t enhance docetaxel. What’s your perspective? Are we barking up the same tree again, or is this different?

Daniel Petrylak, MD: I think that’s a great question. I think it’s a little bit different. When those trials were all designed after the SWOG study and after the TAX-327 trial, I think everybody was looking to get into the game of having their drug married to docetaxel and then moving forward. We understood the biology to some degree, but we didn’t understand it that well. Now I think we’re really understanding the biology better; docetaxel is still a great drug for this disease. It’s hard to knock it off as a comparator arm. You’ve got to move the bar up much higher to see it.

Nicholas Vogelzang, MD: If you’re a betting man, are you going to bet that the immune checkpoints are going to add something to docetaxel?

Daniel Petrylak, MD: I’ll bet on that. But you know the other line too is that 1 in 20 trials are going to be positive based upon statistics. We’ve got to have 1 positive study. But no, I think there’s good reason to be optimistic with these.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Publication Bottom Border
Border Publication
x