Should Checkpoint Inhibitors Ever Be Used Outside of a Clinical Trial in Prostate Cancer - James Gulley

March 25, 2021

In a comprehensive discussion led by Charles Ryan, James Gulley delves into the role of genomic testing and immunotherapy in treating prostate cancer. Dr. Gulley emphasizes the importance of personalized treatment, highlighting studies that identify specific genomic markers like homologous recombination deficiency and mismatch repair deficiency. These markers can guide the use of targeted therapies like PARP inhibitors and PD-1 inhibitors, respectively. He also discusses the potential of CDK12 mutations as a new avenue for immunotherapy. The conversation explores the multifaceted impact of combination therapies, such as cabozantinib plus atezolizumab, on both the tumor microenvironment and immune cells. Both experts agree on the need for more clinical trials and updated genomic testing to better tailor treatments to individual patients' needs.


James L. Gulley, MD, PhD, Chief, Genitourinary Malignancies Branch Senior Investigator Head, Immunotherapy Section Director, Medical Oncology Service, CCR Office of the Clinical Director, Center for Cancer Research National Cancer Institute, Bethesda, Maryland

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation, Minneapolis, Minnesota

Read the Full Video Transcript

Charles Ryan: Hello, and welcome to another installment of our series of talks on the provocative questions in prostate cancer. These questions supersede many of the clinical trials that we are seeing and the big questions that have arisen.

I'm delighted to be joined by Dr. James Gulley. James Gulley, MD, Ph.D., is Chief of the Genitourinary Malignancies Branch at the NCI. He's also a Senior Investigator and Head of the Immunotherapy Section there. So, really, he's one of the nation's top investigators in the area of immunotherapy, coming to us from the NCI. Thank you so much for joining us today, James, who is going to give a brief talk, and then we will have a little Q&A on the topic.

James Gulley:
Well, thank you so much, Chuck. This is a fun area for me. I love prostate cancer, and I love immunotherapy. I want to start by just talking a little bit about genomic testing for cancers, specifically for prostate cancer, and you will see why in just a little bit.

So, you can either do genomic testing for prognosis or for really predictive markers. What we are really going to focus on is the latter. There is a really good study that was done a couple of years ago. It was composed of seven international consortium centers. The lead author was from Memorial Sloan Kettering. They basically took 444 samples from 429 castration-resistant prostate cancer patients, and they looked at them. Now, a lot of times when we treat castration-resistant prostate cancer patients, we lump them all together. Everybody has castration-resistant disease. They all get Zytiga or something like that.

What I want to just highlight is that really each patient is different. What they did was show that there was a group of patients who have homologous recombination deficiency, and this is important because last year rucaparib and olaparib were approved as PARP inhibitors for BRCA mutated patients that fall in this HR deficient category. There is also this tumor suppressor deficient category that they identified, and this is a much bigger category. These include patients that have PTEN loss, P53, or RB mutations. Often this is associated with neuroendocrine dedifferentiation. These patients often do well with treating a little bit differently than the standard castration-resistant prostate cancer, and a subset of these patients actually have small cell prostate cancer. Those patients actually do well with platinum plus a PD-L1 inhibitor, such as atezolizumab.

But I want to focus on these patients here that have MMR deficient prostate cancer. This mismatch repair deficiency. What happens when you have mismatch repair deficiency is you get a lot of mutations, and this is important because that is how the immune system sees cancer. Let me just walk you through this briefly. If you have a cancer cell that has a lot of mutations, these mutations will be translated into proteins that have these mutations, and these proteins made up of peptides will be presented; the peptides will be presented in the MHC molecule on the surface of the tumor cell. And this T cell, that's going by, if it sees this blue, normal self-antigen target, it's going to just shrug and keep going. But if it sees something red there, this neoantigen, this mutation, it's going to say, "Okay, there is something different here. This is not self. I need to attack this." That's how T cells can really look at whatever is made by the tumor cell.

Now, this was a beautiful study, again done by Dr. Wassim Abida at Memorial Sloan Kettering. And what they did is they looked at over 1,000 patients with prostate cancer. These weren't just castration-resistant prostate cancer patients though. These included localized disease. What they found was 32 of them were MSI-high, had microsatellite instability, this mismatch repair. We are going to come back to this in just a little bit. Out of those 32 patients, 11 patients were treated with PD-1 inhibitors. Now, of these MSI-high, a proportion was two-and-a-half percent in the non-castration-resistant prostate cancer. But once you develop PET castration-resistant disease, you see about 5% of those patients had MSI-high. So, one in 20 patients with castration-resistant prostate cancer is MSI-high.

Now, why is that important? Well, if you go in and look at those 11 patients that they treated with PD-1 inhibitors, what you can see is that six of these 11 patients, or 54%, had PSA 50 responses. So, PSA declines by at least 50%. And of these six patients, five had a disease that was measurable by RECIST. And four of those five patients had radiographic responses. If you look at this, it wasn't just a transient response. At the time of publication in May 2018, five of these six patients had ongoing responses for as long as 89 weeks.

We had a patient that was MSI-high also here at the National Cancer Institute, and I'm just sharing with you his data because I think it is kind of interesting. This was a patient who we started on a trial, a vaccine with an immune checkpoint inhibitor, in this case, nivolumab, and you can see the patient had a beautiful decrease in his PSA and it went undetectable. In fact, he developed a complete radiographic response and complete symptomatic response too because he was symptomatic before starting the study. About week 85 here, he developed some colitis, had to come off of the nivolumab, still in a complete response, and he continued getting vaccine just once every three months. He has now been on for almost four years with just getting one vaccine every three months and still remains in complete response with an undetectable PSA.

So, MSI-high, well, that's really only a few percentages of patients. This is a different data set. This is from Dana Farber, and this is an unpublished data set that is being used with permission here. But I want to share this dataset because it's very interesting. In May 2017, that's when pembrolizumab was approved for MSI-high cancers. It was the first tissue-agnostic approval by the FDA and very historic for that fact. So, any cancer that is MSI-high can be treated with pembrolizumab. In June of last year, the FDA approved pembrolizumab for TMB or tumor mutation burden high cancers, any tumors that have 10 mutations per megabase or higher.

So, while you see here in this data set that had a lot of localized prostate cancers, you see about 2% of the patients are MSI-high. About 23% of the patients were TMB-high. This again suggests that there may be a bigger proportion of patients that might benefit, but you would have to get the testing first. Now, the one caveat I would mention here is that we have no data on if patients with prostate cancer who are TMB-high are going to be likely to respond to immune checkpoint inhibitor therapy. But it is approved for that indication.

The question is, are there other types of cancer patients that we can do genomic testing on that may be responsive to immune checkpoint inhibitor therapy or immunotherapy? There is one other subset of patients, and this is really an emerging story. It's still early on in the storyline, but these are the cyclin-dependent kinase 12 mutated patients. Really, this CDK12 controls the expression of DNA damage response genes, and mutations lead to significant genomic instability and thus lots of mutations. So, patients with these CDK alterations that are treated with PD-1 antibodies, you can see nice decreases in PSA in a number of these patients. You can see that some patients can have kind of prolonged progression-free intervals. This patient is up for over 15 months now. What proportion of the patients have these CDK12 alterations? Well, in a paper that was published about a year and a half ago, the proportion was about 5% again. So, similar to what MSI-high is in prostate cancer.

How about other options down the road? This really comes to combination options, and this was a beautiful presentation by my good friend, Dr. Neeraj Agarwal at ASCO GU last year, looking at cabozantinib plus atezolizumab. Now, cabozantinib can do a number of different things that are important for the immune system. Basically, it can interact with myeloid-derived suppressor cells and regulatory T cells to decrease their function or number, and it can enhance cytotoxic T cells. All of this can make it easier for the immune system to either recognize upregulation, for instance, of MHC class I, which is how the T cells recognize, or decrease the negative immune regulatory environment.

What you can see in this interesting combination study is very nice waterfall plots, whether this is by RECIST, as shown on the plot on the left here, or by PSA. You can see in the swimmer plot here that the duration of responses was also quite interesting. There is an ongoing Phase 3 study of this combination. So, stay tuned; maybe we'll see more down the road from this combination.

Charles Ryan:
Okay. Thank you. Great talk. Brought up all the issues that I think we are confronting, which is MSI-high; I have a few questions about that. The setting of CDK12 and in the non-selective group.

So, let me start with the MSI-high. I've had a couple of experiences, as I think a lot of us have, where we've had these tremendous responses. You had highlighted a patient who's been on therapy for a long time. I guess the question is, is there ever a stopping point? Do we know? Should that patient still be getting checkpoint inhibitor therapy? And I wonder, are there late complications of the checkpoint inhibitor therapies that one would worry about in this setting? And, of course, is there a resistance issue that could develop? How do you see resistance developing?

James Gulley:
Some great questions. In this one patient that I showed you that has been on the trial for about four years now, he stopped nivolumab now almost two and a half years ago and has not recurred. So, N of 1. We are holding that in our back pocket so that if he ever does get an increase in his PSA, which we are following very closely, we can go back on the nivolumab. Because the colitis that he had was manageable, treatable. We just said, "Well, you're undetectable now. Let's hold off. We have a very sensitive marker for you."

To look at this in a broader scope, I think we can take some information that we are learning from the melanoma field. There are some data that has come out of Australia where patients with melanoma, if they've had a complete response, then we will treat them six to 12 months after that, and if their response remains, they will come off the study and then we will watch and wait. If they are PET negative and CT negative, we will bring them off the checkpoint inhibitor and hold it. I think we are going to start to see randomized discontinuation trials. There is a move on to look at some of these, and there are some of these ongoing now. That should give us data; is it safe to stop once you get a CR? Kind of like we do in lymphoma where you treat for a set number of cycles after the CR.

Charles Ryan:
Yeah. I mean, there is a randomized discontinuation study for kidney and bladder cancer in the Alliance right now for patients with checkpoint inhibitor complete responses. So, yeah, I'm not sure we will get the numbers in prostate cancer to do it, but certainly, if all of the trends towards telling us that it's okay to do that, then I think this would be something that would enter the standard of care in prostate cancer.

CDK12 is really interesting. I've seen it a few times. I tend to see it in the context of multiple other mutations, and that is one of the challenges and one of the things I want to get across to the clinicians watching, is that context really matters, at least as I think about it. If you're seeing an isolated pathogenic CDK12 mutation, that would probably push me in a direction. But what's your feeling on the sort of the other genomic context that may mitigate or enhance the immunogenicity of the CDK12 mutated tumor?

James Gulley:
That's a really good question. It's an emerging area that I think there is ... The way I approach it is the more mutations one has, the more shots on goal the immune system has to recognize the tumor. There are multiple different HLA types, so not every mutation is going to be seen by every ... If it's one mutation in one patient, it is going to be seen differently than the same mutation in another patient. That being said, a CDK mutation as a single mutation in the background, and has very few scant other mutations, I find that they are less likely to respond to immunotherapy. Whereas if you really are having issues with those DNA damage response pathway genes and the CDK is clearly messed up, then you are more likely to have a response to immunotherapy.

Charles Ryan:
So you would support than an off clinical trial community patient who we do next-generation sequencing, we find a CDK12 really along any spectrum, you think it's reasonable for us to consider that patient ideally for a clinical trial, but even outside of a clinical trial, perhaps that one could reasonably expect that as checkpoint inhibitor may have some benefit.

James Gulley:
Yes. I think there is a reason to expect that. I think that the numbers really are still limited with CDK12. If one has kind of burned through the abiraterone, enzalutamide, and there are still discussions about what to do next, then maybe this is one of the options that one could pick from depending on discussions with the patient obviously.

Charles Ryan: S
o my final question is the cabozantinib data. Are we seeing a tumor microenvironment effect that is making, because of the cabo, that is making the tumor more responsive to the atezo or the checkpoint inhibitor? Or is there something that is happening to the tumor cell, the malignant cell itself, that is doing this?

James Gulley:
I think there are several things that all probably play; it is probably multifactorial. There is a direct impact on the immune cells in the periphery. There's the impact on the immune cells in the tumor microenvironment, those regulatory cells that it decreases function. There is also the impact on the tumor cell itself with the upregulation of MHC. There are some older data suggesting that prostate cancer, in general, has relatively low expression of MHC class 1. If you don't have the MHC class 1 expressed, your T cells are not going to have any way of knowing what is going on inside the tumor, or knowing if there are any mutations there. So it probably is a multifactorial issue with cabozantinib, which is a good thing.

Charles Ryan:
So your closing thoughts on the role, your closing statement on the role of checkpoint inhibitors in prostate cancer. What should we do more of? What should we do less of?

James Gulley:
First thing, what we should do more of is we should definitely get more genomics on patients with prostate cancer. We should not just rely on their original biopsy or their original prostatectomy specimen. We should try and get more recent tissue.

The second thing, that should guide us on what we do. We shouldn't bin everybody with castration-resistant prostate cancer into one bin. We should be thinking about this as different biologies. Because of that, each of those biologies has different Achilles heels that we should be able to focus on. If they have MSI-high, I think they are good candidates for immunotherapy. I think if they have TMB-high or CDK-high, those are still emerging areas; we need, I think I would like to see more data, but it's still on the table for them. Those are areas that we could definitely give immunotherapy. Then thirdly, I would say, really, we need to do more clinical trials. We need to encourage patients, especially patients that have more rare genomic underlying abnormalities, to enroll those patients in clinical trials.

Charles Ryan:
Great answer. James, thank you so much. Lots of great insights to unpack on the role of these therapies in our patients with prostate cancer along the full spectrum of stages. I always enjoy listening to you talk and learn something every time. So, thank you very much for your time today.

James Gulley:
Thank you, Chuck.

Charles Ryan:
All right. Take care.