Personalized Approaches to the Treatment of Prostate Cancer - Kenneth Pienta and James Gulley

Ken Pienta, MD, discusses the role of prostate-specific membrane antigen (PSMA) in facilitating personalized medicine as an imaging agent and selection tool for assigning patients to targeted therapy. He mentions the myriad of trials on PSMA radio-ligand therapeutics that have validated its effect in patients for metastatic prostate cancer. James Gulley, MD, Ph.D., FACS, gives an overview of genomics-based therapies. He discusses that the PARP inhibitors have demonstrated improved survival in patients after progression on other therapies. This discussion is paired with a question and answer portion featuring Alicia Morgans, MD, MPH, and Neal Shore, MD, FACS. They discuss current genetic testing methods for prostate cancer tumors and the benefit of biopsies as well as CT PET PSMA scanning. Dr. Gulley emphasizes how precision medicine can help find the right treatment regimens for patient groups facing different disease trajectories.

Biographies:

Kenneth J. Pienta, MD, The Donald S. Coffey Professor of Urology, Professor of Oncology, and Professor of Pharmacology and Molecular Sciences, The Johns Hopkins Hospital, Baltimore, Mayland

James L. Gulley, MD, Ph.D., 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

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Neal D. Shore, MD, FACS Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina.


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Northwestern University, also, an Associate Professor there. I am so excited to have here with me today, two speakers who presented on personalized approaches to the treatment of prostate cancer and how they impact our decisions now and will in the future. We have two wonderful people here today, Dr. Ken Pienta, who is a Professor of Urology and the Director of Urology Research at Johns Hopkins University. And we have Dr. James Gulley, who is Chief of the GU branch and the Director of Medical Oncology Service at the NCI. So a wonderful group of people today to talk about personalized approaches to the treatment of prostate cancer. Dr. Pienta, can you start us off with your discussion of PSMA?

Kenneth Pienta: Thanks, Alicia. It's a real pleasure to be speaking to you this afternoon. We have the opportunity to think about how personalized medicine, both at the level of genomics, genetics, and imaging and therapy are starting to impact us in the GU field and really think about what's happening. I had the pleasure to talk about prostate-specific membrane antigen theranostics. If you think about PSMA as a transmembrane carboxypeptidase that's highly expressed on all prostate cancer cells, we've seen the power of this PSMA in imaging already. We know that we're asking many questions around imaging; can preoperative staging in high-risk patients be improved? Disease we detected in early biochemical recurrence? Can we guide focal therapy for oligometastatic disease? Can we use it for image response in treating lesions? All those are great questions and we all know that PSMA is in front of the FDA to try and have it approved as an imaging agent.

But what I focused my talk at the AUA on really, can we utilize this imaging agent to select patients that would benefit from PSMA targeted therapy? And then can we actually treat patients? Of course, we're awaiting the results of the VISION study, which is PSMA lutetium-177 over the course of several doses to see if that would help people live longer. That trial will read out in about a year, but in the meantime, there has been a myriad of trials, small trials that have been done looking at PSMA lutetium-177 as a therapy for metastatic prostate cancer. If you look across all of those trials, what you see is that PSMA radioligand therapy has an effect. About 70% of all patients will respond with a decrease in their PSA. If you look at them for disease response, you'll see it. By imaging, about 40% of patients actually have a response that's greater than a 50% drop in their PSA. On the other side of it, about 30% of patients don't respond at all to PSMA lu-177.

There is no question that this is an effective agent. It is not a home run by itself. How it gets developed in the future, we'll see. We also know that there's a lot of excitement around the alpha particle agents, especially actinium-225. And again much earlier, you see that a higher percentage of patients respond to actinium PSMA therapy, radioligand therapy, but there's also added toxicity. You see the PSMA radioligand is taken up by the salivary glands, and we're always worried about dry mouth and you see that a lot more with actinium. So my conclusions from that talk were that there are multiple indications, where we think we're going to see the diagnostics using PSMA, and they will also be used to guide therapy. It's effective, well-tolerated when you look at the beta particles, lu-177. How we increase their effectiveness in combination or with other agents, we don't know yet. Actinium will continue to be developed. There are antibody versions. There are small molecule linker versions. PSMA therapy is going to be in our future. We just don't know how yet.

Alicia Morgans: Great. Well, thank you so much. That was a great summary of the talk that you gave at AUA 2020, which is really helpful. As we think about this from the context of the urologist point of view, Neal, what questions do you have for Ken?

Neal Shore: So, yeah. Ken, great summary of the presentation you did at the AUA live. Just to put it into context, so both Ken and James were asked to give their presentations as the best of the best for the area in Washington, DC, Mid-Atlantic in our forum, the International Prostate Forum. They were gracious enough and they really are the best. Their body of work is amazing. Ken, in a matter of three or four minutes, gave an exceptional, a really pithy, concise overview of what's going on in PSMA diagnostic imaging and how it's going to change what happens in the United States as it has in other parts of the world to have accessibility, but not only from a diagnostic standpoint in detecting disease with much greater accuracy than conventional scanning and images but also how we tie it into a theranostic or a therapeutic aspect.

So, as he said, it may not be a home run, but for some patients, maybe it will be in terms of who those who are the great, really good responders. For urologists, I think it's really important to recognize that the VISION trial will be in heavily treated patients with mCRPC. But as Ken said, it's going to move approximately like all of the other CRPC therapeutics. So, Ken, my only question for you is I have a zillion of them, but we only have so much time is what are your thoughts about if and when lutetium-177 gets approved, will that change the incorporation of its use with the multidisciplinary team? Have you given thought about that for urologists, nuclear medicine, radiologists, medical oncologists, and radiation oncologists?

Kenneth Pienta: Well, we think about that all the time, Neal. I think it's a great question. We always do move these therapies up as fast as we can to the treatment-naïve setting instead of six lines of therapy, one line or two lines of therapy. I already know anecdotally of many men who have traveled overseas to get PSMA lutetium therapy to avoid hormone therapy when they have metastatic disease. We're doing a study right now looking at can you treat micrometastatic disease with the lutetium-177 PSMA even before you can really see it on scans? It's still going to get taken up. So I think you're going to see, as these agents get approved, that you're going to see them earlier and earlier just like we did with the abiraterone and docetaxel, olaparib, and every other therapy. How we mix that in with the other treatments, it's going to be fun to see.

Alicia Morgans: Great. Ken, I wanted to ask you also about imaging, which was another part of your talk and so relevant to the urologists who are watching for men with a high-risk or intermediate-risk localized disease, men with biochemical recurrent disease. There are tracers, PSMA targeted tracers that are on their way and that we hope will be approved in the near future. What are your thoughts about that and how do you feel those are going to be integrated into the urologist practice?

Kenneth Pienta: So I admit that I have very strong feelings about that. I believe that any patient with high-risk disease that's just recently being diagnosed deserves a PSMA scan to determine if they have disease outside of the prostate. We have studied that. We've done trials in that. I know that the NCI has also. It's very important. You can really see clinically micrometastatic disease in the lymph nodes and often in the bones, it should change therapy. It forces a multidisciplinary approach, and I feel very strongly that that will become the standard of care, that we will stop doing bone scans and just plain CT scans.

PSMA CT is going to be the new standard for men with newly diagnosed, high intermediate, and high-risk prostate cancer. Similarly in the biochemical recurrent space, it is an extremely powerful tool to find disease that's not clinically evident by a CT scan or a bone scan that can guide therapy. We can play whack-a-mole and hit a single metastatic site, and that's often effective. That's going to take a lot of study down the line, but in the newly diagnosed patient, I think it's going to become the standard of care.

Alicia Morgans: Great. Well, Neal, I want to give the last question for Dr. Pienta to you. What question do you want to ask?

Neal Shore: Well, he sort of alluded to it, but I'm going to bring it back because I want people to really appreciate this is yeah, once we get PSMA diagnostic imaging approved in the US, and there are two different pathways for that right now, UCLA and UCF to their credit have an application in front of the FDA, and then also Progenics has a PYL FAT. I know Ken, you've been very involved in that. So just again, I wanted to get back to this notion around using traditional conventional technetium bone scans and multi-slice CT scans. Do you see a time in 2021, perhaps where it's going to be CT PET PSMA scanning is going to be the standard?

Kenneth Pienta: I can only hope that we make it by 2021, if not 2021, 2022. But whether you use the gallium imaging agent or you use the FAT imaging agent, both are extremely sensitive and specific. For the metastatic disease, you can pick up about a BB size of cancer in the nodes or in the bone, and that will replace both modalities and should. Of course, nobody's talking about doing those imaging studies with PSMA without a CT scan because it's a merged image and you really need them both, but that should become the standard of care and I know James feels the same way.

Alicia Morgans: Well, great. Well, let's move on to James and his discussion of genomics, genetics, and the way that they are really playing a larger and larger role in the treatment of prostate cancer. So we'd love to hear from you, Dr. Gulley.

James Gulley: Thanks so much, Alicia. So I had the pleasure of talking about what's happening in prostate cancer, especially in metastatic prostate cancer with genomics. We are now starting to see that there are more and more therapies available based on genomics. So we went through some of those. We talked about really what's happening with the DNA damage response pathway mutations and what was at the time, the talk was recorded, there was nothing yet approved, but there was hope that it would soon be approved. Sure enough, on April 15, you had the approval of rucaparib for prostate cancer and in April... Sorry, not April, both of them in May 15 and May 19, you had olaparib approved for prostate cancer. The rucaparib of being approved as a result of the TRITON2 study and that was an accelerated approval. So not full approval, but it was approved based on an objective response rate of 44% and a prolonged response with over half of the patients maintaining their response at six months.

Olaparib got approved just a few days later with regular approval for any HR deficient cancer, and it got regular approval. It also came out with two different companion diagnostics with foundation medicine. But what we're seeing now is that patients that have progressed on abi or enza, these are the types of patients that we really need to go in and get a biopsy of these patients to figure out what's going on because these PARP inhibitors really can dramatically impact the response rates of these patients and the survival as is shown with the olaparib improving survival. You see about 15% of patients have these DNA damage response pathway gene mutations, so this is a real number of patients. In addition, we talked about microsatellite instability and the approval by the FDA of pembrolizumab for microsatellite instability. We also talked about the fact that that's about 5% of patients that have progressed on abi or enza. Now, that's a pretty decent number.

Recently, however, since the time the FDA approved the use of pembrolizumab for any high tumor mutation, so any patient that has a tumor mutation burden of 10 mutations per megabase. So it looks like there's going to be a lot more of those than just the 5% in prostate cancer. So stay tuned on that. We don't have data yet on the percent of patients who have responses with a tumor mutation burden, high prostate cancer and pembrolizumab.

We also talked about the neuroendocrine dedifferentiation and the correlation with PTEN loss and p53 loss and RB loss. If you have all three, you're about anywhere from 12% to 18% of the patients have that based on those criteria for genomic loss. And really, you do better if you give chemotherapy combinations when you give it with a platinum agent plus or minus, if it's a real small cell histology, then you probably want to use an immune checkpoint inhibitor and atezolizumab is approved with platinum combinations there.

Then there are a potential for TREK fusion proteins. These are rare to be seen in prostate cancer, but there is an FDA approved agent for that. So really, I think in order to have the optimal treatment options for our patients that have metastatic castration-resistant prostate cancer, that have progressed on either abi or enza, we really need to biopsy these patients, do the genomic analysis and that can drive the treatment options. It can also help us understand what's going on with their disease. So I think this too, for real, we need to take this seriously and really get more biopsies on these patients.

Alicia Morgans: Well, thank you. That was a wonderful summary of what you presented at AUA 2020 meeting. Neal, I will give the first question for Dr. Gulley to you.

Neal Shore: Thanks very much, Alicia. So, James, yet again what a great presentation and thank you for presenting at the AUA and the work that you've done. The thing that I want... Why we chose John Davis and I, when you gave us a couple of options of what you wanted to talk about, thought that this was so incredibly important that the message out there for community urologists worldwide, US and outside the US, is the importance of doing the testing. You can't give any of these therapies. You can't give a checkpoint inhibitor. You can't give a PARP inhibitor if you're not tested. You can't know to potentially give a platinum combination. So, James, can you tell the urologists out there in the community, what are your recommendations and guidance for testing patients? And for me, I can just tell you, I know I've really been very aggressive and liberal in expanding who I test. I always just try to think of almost everyone should get tested except only a few, but what are your thoughts on testing and how to test?

James Gulley: Great question. So, first of all, I would love to be able to, at the NCI, we would love to be able to test everybody coming in the door, just wherever you are in your cancer, let's test now and then when there's a decision point. I think for the general community practicing doc, the decision point for me, because abi or enzalutamide really are so effective for the majority of patients, I would say that once they progress on that, the chances of response are dramatically lower to the second agent.

That's really where you want to go ahead and test. How you test, you can get some analysis from germline testing, but I really think somatic testing, actually biopsying the tumor, getting that analysis really is going to be key for a lot of these therapies moving forward. I think that we're working on ways of doing liquid biopsies. Right now, that's really not completely ready for prime time yet. I know that some of these lesions are difficult to biopsy, but if you have a biopsy accessible lesion, I would recommend getting that and then sending it off to FoundationOne® or some other entity that can do the genomic testing for you.

Alicia Morgans: Great. Well, I think that's perfect advice and I would absolutely agree. In real practices sometimes, of course, there are patients who have bone predominant metastases and that can be less reliable, especially with variation between site to site. It's not uncommon that folks ask me, "Well, I did a prostatectomy three years ago, and I certainly have sufficient tissue. Is that a reasonable option?" If I know that circulating DNA testing is not necessarily ready for prime time, I have the tissue, is that reasonable? What are your thoughts on that?

James Gulley: Yeah, so I actually, I think this would be an individual thing, but absolutely anything is better than not having any tissue. There is a chance you will miss cancer as it progresses. You have not only heterogeneity that you mentioned where one lesion can be one thing and another lesion can have another genomic profile, but you have heterogeneity over time. The cancers evolve over time and you have tumor cells that outgrow other cells. Often, you see over time, the cancer gets more and more dedifferentiated, more and more genes are kicked out, more and more mutations accumulate. So you may be missing some potential options if you don't biopsy, but you also may be catching that BRCA2 that was there at the very beginning. It's a low hanging fruit to send that off. The genetic testing is becoming much cheaper to do, so I would start with that. If you don't see anything, then figure out whether it makes sense to actually biopsy.

Alicia Morgans: I really appreciate that because I do think, like you said, some of these BRCA mutations can be sort of, they can be truncal, early mutations and they are going to be present in the prostatectomy. So if you don't have another source of tissue, that is a place where you might be able to find a targetable mutation that occurred early on, but certainly, as cancers evolve, particularly if we see they spread to the liver, for example, that's always something I look into biopsying because you might have more viable tissue there. So great advice. Neal, I will throw the last question back to you.

Neal Shore: Well, thanks, Alicia. I'd love for you to maybe, James think about how we have treated so many patients with sort of a blunt instrument of therapeutics, but now in the era that we throw these words around, "personalized and precision," what do you think in terms of the future, especially in our advanced prostate cancer patients, whether they're androgen-sensitive or castration-resistant in terms of the different lines of treatment that one would want to be thinking about? Because it's really no longer going to be a one size fits all. Even Ken alluded to in his presentation that maybe in biochemical relapse patients, we won't start them on testosterone suppression. Maybe we'll treat them with a targeted radionuclide, but I wanted you, James to maybe comment on your thought processes about these different buckets of where patients would come into play in terms of therapeutic options.

James Gulley: Yeah. So really great question, Neal, and you're right. We have historically, we've been treating patients and we've started out with hormonal therapy. Then if they've progressed, then we give another line of hormonal therapy and then eventually chemotherapy. Then we kind of wash our hands and do supportive care type of thing. As over the last 10 years, that's evolved where we've gotten more and more agents, but largely targeting the AR pathway or radium 223 is novel, sipuleucel-T is a novel mechanism of action. But what we're finding now with these genomic testing is potentially, you could intervene earlier. Instead of just this sequential, you could now do combination therapy earlier. You could look at, does it make a difference if somebody has a BRCA mutation if you treat them with PARP plus enza or something like that early?

I guess, kind of big picture thing, one of the things that I have been struggling with is this is great. We're moving the needle, but I don't want to move the needle just a couple of months down the road. What I want to do is I want to figure out ways that we can actually cure these patients. So some of the opportunities to take immunotherapy and combine it with PARP inhibitors or other things that rationally makes sense, and we've seen some interesting things in the clinic happening, or those patients that are MSI high; could we take them early on and give them the immunotherapy in combination, perhaps with hormonal therapy, but lead to cures?

We had a patient that's MSI high that we put on a study where we gave him a vaccine plus PD-1 inhibition, and he had a complete response with bone scan normalizing, soft tissue normalizing, PSA going to undetectable. Eventually, he had to come off of the PD-1 inhibitor and his PSA has remained undetectable now for 16 months since he's been on the PD-1 inhibitor. So I think there are opportunities there. We just have to figure out the right combinations in the right patients. I think looking at the genomics of those patients is going to be critical to evaluating how to approach these patients. If we have an opportunity to add in combinations of therapies that can lead to cure, I think that's where we want to go.

Alicia Morgans: So I think that is a wonderful way to wrap things up. I think all of us and probably all of the people listening and watching are of the same mindset. We all want to cure this disease. As we've seen in other solid tumors, sometimes we put things with different mechanisms of action together, those combinations are able to attack the heterogeneity that we know exists in these cancers, and hopefully, we'll be able to eradicate disease. So thank you both for your time. Thank you, Neal for your time. And thank you all for watching this AUA 2020 update.