Best of ASCO 2020 Prostate Cancer - Oliver Sartor

Oliver Sartor joins Alicia Morgans to speak about several prostate cancer studies making an impact on the diagnosis of prostate cancer and the treatment paradigm for this disease. They highlight 68Ga-PSMA-11 for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic Lymph node dissection and the CONDOR study on the impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer after definitive local therapy with the potential for an FDA approval. The third trial they discuss is a Phase II PSMA theranostic study, the TheraP trial of PSMA-617 Lutetium 177 theranostic vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (mCRPC).  Finally, Dr. Sartor discusses two additional ASCO 2020 presentations, two first-in-human phase I studies, ARV-110, an androgen receptor PROTAC degrader, and HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, both in patients with mCRPC.


A. Oliver Sartor, MD, Professor of Medicine and Medical Director, Tulane Cancer Center; C. E. and Bernadine Laborde Professor of Cancer Research, New Orleans, Louisiana

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.

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Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so happy to have here with me today, friend and colleague, Dr. Oliver Sartor, Professor of Medicine at Tulane and the Medical Director of the Tulane Cancer Center. Thank you so much for being here with me today, Oliver.

Oliver Sartor: Well, delighted to be here, Alicia, and get to see you as well.

Alicia Morgans: Wonderful. We on the heels of ASCO really wanted to do a bit of a roundup to talk about some of the exciting abstracts that have been presented at ASCO, the virtual meeting, 2020. And I think there were a few key topics that we wanted to hit on in today's recording. The first is really to focus on the abstracts that are looking at methods of PSMA imaging using this more targeted imaging technique in a couple different populations. The first was presented by Tom Hope and is a gallium PSMA approach to looking at patients who have high-risk or intermediate-risk localized prostate cancer, Phase III trial. Can you tell us a little bit about this gallium PSMA study, Oliver?

Oliver Sartor: Yeah, absolutely. It's an important study by Tom Hope out of UCSF. Exactly as you stated, they looked at intermediate- or high-risk prostate cancer. This is prior to treatment. They had 277 patients that had a scan and then underwent radical prostatectomy with lymph node dissection. And really what they were trying to look for was how good was the PSMA scan at detecting lymph nodes? And just a little bit about the scan. This is a gallium-68 scan. This is going to be a little bit distinct from the other PSMA ligands that we're going to discuss here a little later, but gallium-68, PSMA-11 scanning. What they did was to look at the lymph node positivity. And first of all, you have to understand that not everybody has lymph nodes. Only 27% of the patients actually had lymph nodes detected at the time of surgery.

And then they looked at sensitivity and specificity. Sensitivity for some, might've been a little bit disappointing at 0.4. The specificity, however, was quite good at 0.95. Simple terms, if you saw something, it was probably real, but if you didn't see something, you could still end up having a positive node. And of course, nothing will ever replace a pathologist looking under a microscope. A lot of these cancers that were node-positive have had microscopic disease. They did find that the sensitivity went up to 0.68 if the node size on the imaging beforehand was greater than 10 millimeters on the cross-sectional scan. And they did find a little higher sensitivity with higher PSA. The PSA medium, which was 11, was greater than 11, then sensitivity got up to 0.48. Overall, I'll simply say that PSMA scan is a really good scan. If you see something you can believe it, if you don't see something, you don't always know because it'll never detect the microscopic involvement. But, it gave us a good picture of evidence when you use PSMA-11 gallium-68 in the pretreatment setting.

Alicia Morgans: Absolutely. A setting in which we want to be sure, if we're going to put someone through surgery, for example, we really do want to be sure that we understand the staging as well as we possibly can. And so if we do see something on those scans, it is probably real, which is really, really important. And of course, the larger the node, as you said, and the higher the PSA, especially over that median of 11 it's probably something we can trust even more and expect that we have a more sensitive scan. Ultimately we hope will be approved for use in the future. And can you tell us a little bit about this gallium approach, which I know is different than the PyL PSMA study, the imaging study that we're going to talk about in just a minute? What are your thoughts on gallium as a PSMA agent?

Oliver Sartor: Well, I'll make a little distinguishing comment about the isotope and the agent and because you have to have something that binds the PSMA. And by the way, in the course of discussions today, we're going to talk about PSMA-11, going to talk about PyL and we're going to talk about PSMA-617. These are all different small molecules that actually bind the PSMA, each in their own way. Each of them bind by the way, in a really good way.

Then we're going to talk about three isotopes. We have the gallium-68, the F-18, and then for treatment, and that's a whole different topic because now we're talking diagnostics. For treatment, we're going to talk about lutetium-177, which is a beta emitter.

The gallium-68, to address your question is a PET imaging agent. And you have to use a generator, it has a relatively short half-life. It's not really cyclotron based, which means that you'd typically have to have a generator either onsite or in a close proximity, and you can get good PET imaging with gallium-68. That's clearly been shown. Some people do prefer the F-18. There's a little bit of data to show that the F-18 might give a slightly higher SUV, a little bit easier detection, but I don't really think there's a huge difference between the gallium-68 and the F-18 in a practical way.

What made govern using it in the future is the availability and the cyclotron takes advantage of the F-18, which I think FDG PET, which is an F-18 based PET approach, is widespread across the country. And if you can make an FDG F-18, you can be able to make a PyL, DCFPyLs, name of the molecule, came out of Marty Pomper's lab at Johns Hopkins. Then you can probably make an F-18 PyL molecule. These are going to be sort of differences in distribution, but practically speaking, not a huge amount of differences as a PET agent.

Alicia Morgans: Thank you. And that's a really nice segue into our F-18 PyL or DCFPyL PSMA PET study that was presented by Michael Morris, the CONDOR study. This is another imaging approach. This is in a population of patients who have already had treatment and now have a biochemical recurrence. On standard imaging, used as a screening for this study, there was no evidence of metastatic disease in terms of a radiographic evidence on conventional imaging. Can you tell us a little bit about your thoughts on the CONDOR study in this biochemical recurrent population?

Oliver Sartor: The CONDOR study, I think is a very important study because it's likely to lead to FDA approval and it's conducted in a different population. These patients were all biochemically recurrent after initial treatment. The vast majority of them, about 85% had actually had a prior radical prostatectomy and about 35% had had a radical prostatectomy and salvage radiation, and then progressed despite both of those prior treatments. There was about 50% of the study that had had radiation alone as prior therapy.

Now, one of the things that I did want to kind of cover is some of the sensitivity that is associated with the PSMA scanning, because this is very, very different than the CAT scans and the bone scans that we're familiar with. For patients with a PSA of less than 0.5, about 36% of the patients actually had a positive finding on the PSMA scan. For a PSA between 0.5 and one, was about 51% had a positive scan. Between one and two on the PSA scale, two-thirds of the patients had a positive PSMA. And between two and five, it was about 85%. And again, completely different results than you would have seen with CAT scan and bone scan, which is critical to understand if we understand this trace sensitive imaging.

But one of the real questions was, how do you determine what is a true positive? And these discussions with the FDA led to some language that's a little bit unusual. One of the things that they wanted to look at was something they called a correct localization rate. And that was actually what the endpoint of the study was. And in order to understand what a correct localization rate is, you have to understand what a standard of truth composite is. And let me go through that because you can't understand the study without understanding what a standard of truth is.

You see a spot on the PSMA, you wonder, is it real or not? One standard of true would it be pathologic confirmation. If you've got a pathology report from that region that showed there was a real cancer, then that was assumed that it was a true positive. If you took that area that had an abnormality and radiated it, and the PSA went down, that would be considered to be a true positive. Why would the PSA go down if you radiate a false spot, it's not going to go down. That was radiation response as part of this standard of truth. And then lastly are conventional imaging. And conventional imaging could include the Axumin® scan, which is another form of PET, the fluciclovine F-18 scan, or yet another form of PET, a choline PET, and an MRI or a CT. And you can get these confirmatory findings. The standard of truth was pathology, conventional imaging, including two PETs, the Axumin® and the choline, or the PSA response to radiation. That's the background.

What did they find? Well, in addition to this sort of nomenclature around correct localization and standard of truth, they had three different readers because they didn't want just one reader being the truth. There are some varying numbers that you get, depending on who was reading the scan, but for the correct localization rate, it was between 84.8 and 87%. Think about that if you will, as a positive predictive value. If you saw something, then the standard of truth of one of these three estimations of what is true, gave an 84.8 to 87% positive predictive value. That's pretty damn good.

And very importantly, these scan results resulted in a change in clinical management. About 64% of the patients after the PSMA scan had a change in clinical management. Seventy-eight percent of the clinicians changed their management plan because of a positive PSMA and 21% changed because of a negative PSMA. This study is important, likely to lead to FDA approval for the PyL F-18 product and really demonstrating clinical utility in terms of changes in management. Very importantly, it did not demonstrate that the change in management would result in a more favorable outcome. That will be a separate study. CONDOR's a little bit complex, but I've hopefully covered it in a way that's understandable and fairly succinct.

Alicia Morgans: I think you did. And I think this was another Phase III trial that looked at a little bit of a different population. Again, the biochemical recurrent population, predominantly in a postsurgical group and found that they were able to identify lesions and then demonstrate that these were truly prostate cancer lesions in this population and also affected treatment choice for patients. I think you covered it beautifully. And I think that this is one of the studies that we've been waiting for both of this and the last study that you talked about because in the United States, we've been hoping for this imaging to demonstrate an appropriate sensitivity specificity and ultimately a clinical utility. And I think we're moving in that direction and I am hopeful that this will lead to an approval as well. Thank you for going through that.

Now, moving away from imaging, as we focused for the first two studies on PSMA and imaging, let's talk a little bit about the TheraP trial. This is a therapeutic trial that looked at lutetium, which was being targeted using a PSMA approach. Can you talk a little bit about the TheraP trial?

Oliver Sartor: Well, first of all, I need to say that I wish I was so clever as the Australians because they always seem to come up with such great trial names and nomenclature. I'm not as clever as they are. The TheraP trial by Michael Hofman, it's randomized Phase II, and I think it's actually really important because it gives us an idea about how the PSMA treatment trials are going to perform. And there are some large Phase IIIs such as VISION that are going to follow, important distinctions between VISION and TheraP. But nevertheless, this is a PSMA-617, that's the ligand, lutetium-177, the beta emitter trial. And the randomization was between the PSMA lutetium-177 and cabazitaxel. A good randomization. All the patients were pretreated with docetaxel. Everybody had metastatic castrate-resistant prostate cancer, and 91% of the patients had had previous treatment with abiraterone or enzalutamide.

This is really a nice trial. What'd they find? Relative to cabazitaxel, the PSMA had a favorable PSA response rate. Sixty-six versus 37% for PSA declines of 50% or more. I thought that was quite impressive. Sixty-six versus 37 with an FDA approved agent like cabazitaxel. The median follow-ups were also altered in terms of hazard ratios. The hazard ratio for PSA progression-free survival was 0.63, highly statistically significant, favoring the PSMA lutetium-177 arm. And that's really good. The grade 3/4 AEs were lower, when using the PSMA lutetium, 32 versus 49%, and only one patient out of 98 actually stopped treatment because of toxicity in the PSMA arm. Overall I think this is a favorable trial. With PSA endpoints we don't really have the rPFS, we don't have the OS yet, don't have enough maturity, but nevertheless, important information in a randomized setting about the efficacy of PSMA-617, lutetium-177.

Alicia Morgans: I completely agree. And I think one of the most exciting parts of this trial from my perspective was how bold they were to actually randomize against a very clearly active control arm. And as you said, an FDA approved agent that we know prolongs life has been recently shown in a Phase IV study, the CARD study, to improve quality of life to some extent as well and have some pain improvements and some other benefits as well in this population. That's an even more heavily pretreated population. But for lutetium to demonstrate a benefit in terms of PSA response, I think that's phenomenal against this quite active control. And really important as we will see it I hope to translate into the Phase III trials that will be coming on its heels in the future.

One thing that I would love to hear your thoughts on, when do we hope and expect that we in the United States may have access to something like lutetium? Do you have any thoughts on that? Obviously we don't have results from a Phase III yet, which would be really necessary for registration and for approval, but do you have any hope in terms of a timeline for lutetium? Many patients ask this.

Oliver Sartor: Yep. The pivotal trial is going to be the VISION trial, which is fully accrued, but has yet to report. It's an event-driven reporting and the number of events have yet to be reached. And there's a primary endpoint is an rPFS endpoint. And then there's an OS endpoint. I can simply say that enough events have yet to occur for reporting. Now, possibly ESMO on rPFS. Possibly, I don't know. But let's just put it this way, I don't think it's unreasonable to think about 2021 as being the possibility of an FDA approval if the pivotal VISION trial reports out positive. Possibly 2021. If, and that's a big if, if VISION is positive.

Alicia Morgans: Well, I thank you for, I know that's it's a guess, it's a best guess, and we will definitely not hold you to it, but it is something that, it is a question that people ask and I think with the TheraP trial, and multiple other studies that the Australians are doing, there is a lot of excitement about this lutetium PSMA agent and we're all excited to see it hopefully come down the line.

There were two other studies that we wanted to touch on from the prostate cancer sessions at ASCO that are novel mechanisms of action. And that I think many of us believe that we're going to need novel mechanisms of action in this disease to really continue to move the needle. And we've been successful over the last few years with them. Two new approvals recently for PARP inhibitors and potentially lutetium in the future. Let's talk a little bit about some of the novel mechanisms of action that were presented at ASCO. There was the Harpoon study, which was a Phase I study looking at this new approach, a TriTAC approach, a tri-specific T-cell activating construct. Can you tell us a little bit about this?

Oliver Sartor: Yeah, so it's quite interesting. It's kind of a variation on the biospecific antibody. Now Amgen has an FDA approved product, the BLINCYTO® product in relapsed AOL, and you basically engage a portion of the cancer cell and then activate a T-cell. And then magic happens and the T-cell kills the cancer cell. And so this is another one of these kind of magical things. They have three binding domains in this TriTAC approach. They have PSMA, which we've talked about already. And then there's an anti-CD3, which I think is pretty familiar to everybody on the T-cells. The third component here is something to extend the half-life, and this is albumin binder. If you make an antibody, you're going to end up with a large molecule that may have a long half-life, but it may be a little bit difficult to control particularly if there's cytokine storm.

If you get to antibody configured such that it's just a piece of the antigen body domains, it can be too small and then not have an adequate half-life. What they did is they took this TriTAC approach and use the albumin binding to prolong the half-life, PSMA binding to get to the tumor cell and CD3 for the T-cell. It's the first advanced study, which I think is important and they used eight different cohorts in their Phase I trial. Turns out they really did not have any evidence of dose-limiting effects. And they did have three patients that had the cytokine storm, the cytokine release syndrome but all three of these were able to resolve in patients to be treated.

It was not a huge commitment of efficacy reported in the abstract, with just two patients with a PSA decline of more than 50%. But eight patients were still on study at more than 24 weeks. Now pretty heavily pretreated patients with the median of six different prior therapies. I'd probably put it at ADT, but we want to look at more data on this. The importance is it's a novel mechanism of action, novel molecule. And of course, that's why it's interesting, at least to me.

Alicia Morgans: Absolutely. And let's conclude with another Phase I study, another first in human, this is a PROTAC targeting, it's ARV-110, and it's a proteolysis targeting chimera. PROTAC is what we're calling that. Essentially I thought of these as androgen receptor degraders or protein degraders. And this was also tested in patients with heavily pretreated, metastatic castration-resistant, prostate cancer. What are your thoughts on this molecule or this agent?

Oliver Sartor: Well, first of all, it's a first in man study and always read those with a little extra interest. And you're exactly right, Alicia. This is about protein degradation. This PROTAC platform could actually target different proteins, but in this case, it's that AR degrader, the androgen receptor degrader that's important. And they had four dose levels and they're in their Phase I. There were no clear DLTs but they did have two patients who had trouble with liver function studies. One of them had bad troubles, but whether or not that's idiosyncratic or not, we just need a little more information.

When they got to what they believe to be a relevant dose, which is their 140 milligram dose, that it turned out they had eight patients in that little cohort and two of them responded and the two responders were actually pretty reasonable. Eight plus, 21 plus weeks. One of them had a PR radiographically, in addition to PSA decline. And again, the reason it's interesting to me is novel mechanism of action, first in man study. And this is a molecule we're going to hear more about, but this is our first one. Anyway, interesting. I think that it will get a lot of buzz when people are talking about new drugs in prostate cancer.

Alicia Morgans: I agree. And that's exactly what we need. We need to optimize our use of the drugs that we have, and we need to continue to advance the pipeline and try to find new treatments for this disease. Well, I sincerely appreciate your time and your guidance of our journey through this ASCO 2020. It's some of the most compelling and exciting abstracts from this year. Thank you so much for your time, Dr. Sartor.

Oliver Sartor: Thank you, Alicia. Always a pleasure.