Transforming The Standard of Care for Men With Advanced-Stage PSMA-Positive mCRPC, Published Results from the Phase III VISION Trial - Oliver Sartor

June 23, 2021

Oliver Sartor, MD, joins Charles Ryan, MD in a conversation about the New England  Journal of Medicine publication "Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer" known as the VISION trial.   The VISION Trial is an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron- emission tomographic–computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Proto- col-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary endpoints were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary endpoints were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.
phase III study assessing lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer and the groundbreaking set of results with the potential to change the standard of care and open up a new modality of options for patients. This is the first phase three study with this class of compound. It has overall survival as an endpoint. People want to live longer and live better and this trial shows both.

Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer supporting its adoption as a standard of care, once it reviewed and approved by the FDA.  


Biographies:

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

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.


Read the Full Video Transcript

Charles Ryan: Hello, Chuck Ryan from the University of Minnesota here. I'm joined today by Dr. Oliver Sartor, who is a Professor of Medicine and the Medical Director of the Tulane Cancer Center, where he is also the C.E. and Bernadine Laborde Professor of Cancer Research, and that is, of course in New Orleans, Louisiana. Oliver played a pivotal role in the development of Lutetium 177 PSMA, which was recently presented as a plenary session at ASCO 2021 and is now published in the New England Journal of Medicine. Oliver, Dr. Sartor, thank you very much for joining us today.

Oliver Sartor: Thank you, Chuck. Really a pleasure to be able to discuss these results.

Charles Ryan: This is really a groundbreaking set of results going to change the standard of care and open up a new modality of options for patients. For those who aren't familiar with this treatment, tell us a little bit about the background of how this treatment works and how it is administered.

Oliver Sartor: I think a lot of people know about PSMA today. That it is a prostate-specific membrane antigen, and it turns out that this is expressed from prostate cancer cells and even more expressed from prostate cancer cells. And it turns out that the ability to image PSMA is something that we all know about with the recent approval, May 27th, of the PSMA PET scans, but treating is not a completely new concept, but it is to some people a new concept.

So, what we do is target that PSMA molecule on the surface of the prostate cancer cell. But instead of bringing a tag that is suitable for imaging, like gallium 68 or F18, we bring a therapeutic isotope to the surface of the cell, and that would be lutetium 177 in this case.  By the way,  there are other isotopes being explored, but today lutetium 177 is the highlight because that is where the study is fairly positive, the phase three study.

Charles Ryan: So we've been talking about PSMA and lutetium on UroToday for quite some time and we've seen a lot of results coming out of Australia and other countries. Tell us about the VISION study and what makes it special.

Oliver Sartor: I think what makes it special is a couple of things, first of all, it's a phase three study. It's really the first phase three study with this class of compound. And number two, to me, it has overall survival as an endpoint, which is incredibly important. There are a variety of other endpoints we could use in the study, PSA response rate, time to PSA progression, but you know what people want, is they want to live longer and live better. And this trial shows both actually. So I think it's pivotal because of the overall survival benefit and the large magnitude of that benefit in these very difficult to treat patients.

Charles Ryan: Right. So let's take a little bit of a deeper dive into the VISION study. This was a study for patients who had received one or more prior androgen receptor pathway inhibitors, and one or more taxane regimens. They all of course had progressive mCRPC. So this puts lutetium in this trial at a very late stage in the disease, but there were some other criteria regarding PSMA expression, which leads us into a little bit of a biomarker conversation. If you could, tell us a little bit about how patients were selected based on PSMA expression and what that means moving forward.

Oliver Sartor: Every patient that entered the trial had a PSMA PET, and we actually used the PSMA Gallium 68 tracer just to be precise about which tracer we used. I'm not sure that the tracer will make that much difference. Every patient had to have metastatic disease as detected by the PSMA PET and the uptake of that metastatic disease had to be greater than whatever was the reference range. We wanted to kind of make it simple.

But we also had some other selection criteria. We were concerned about lesions that might be PSMA negative. So every patient also had cross-sectional imaging like a CAT scan. And then we looked around to see if there were lymph nodes greater than 2.5 centimeters that were PSMA negative. If so, that patient could not be enrolled in the trial. Or if they had visceral lesions that were greater than one centimeter and PSMA negative, those patients could not enter into the trial. But it turns out about 87% of the patients that we actually PSMA PET scanned actually were eligible for the trial. It was a little bit higher than what I was expecting, but the bottom line is we did use PSMA PET as a selective biomarker for trial entry.

Charles Ryan: Moving forward. The question has come up as to whether or not PSMA is a marker that becomes more expressed as the disease progresses, or is this ubiquitous in space and sort of ubiquitous in the time biomarker. Are we likely to see PSMA expression on untreated prostate cancer?

Oliver Sartor: We are. If we look at the imaging trials that have come out of UCLA, UCSF, and now broadly throughout multicenter trials, what we see is a very high level of PSMA positivity. Not everybody, but the vast majority. How well this will be carried forth as a predictive biomarker is going to be in part dependent on the future studies that are done. I think what we did in VISION is done. We did use this as the selected biomarker. 87% were positive. Could you leave off the scan and still have a positive study? Probably so, to be honest with you, because the hazard ratio on the OS was 0.62, and the p-value was many zeros and a one. So it could be that you didn't even need to select, but we did. And I think the question will be as we go forth, how will the regulators respond to this? No PET, use a PET? I'm not quite sure. We will see how that discussion plays out.

Charles Ryan: It's a really interesting point because it could point us to a time when we could perhaps save money by not doing those PET scans, but run the risk of over-treating some patients or patients who don't have the biomarker, and we will look forward to future publications and thoughts on that. In the VISION trial, the lutetium 177 was given every six weeks for four cycles and could be increased to six. In the control arm, it was a protocol permitted standard of care, which consisted of a whole host of treatments. What can you tell us about the durability of the treatment? In other words, how many patients were able to take all four treatments, maybe increase it to six? I guess this speaks to both its efficacy and its safety.

Oliver Sartor: The median number of cycles was five, and many patients received six. So the majority of patients actually received five or six cycles. The option was given of extending beyond four. So four was kind of where the investigator was supposed to pause and then say, "Okay, is the patient having benefit? If so, we can give two more." So six were not required. Four were required. Now, as it turns out, there are always going to be some patients who don't even make the four. It was less than 10% that dropped out after one dose. Some patients are going to rapidly progress, I hate to say it, even after good therapies. And probably about 20% of the patients did rapidly progress. So not everybody got to four treatments. Regardless, the treatment was very well tolerated in terms of discontinuations due to toxicity, in terms of dose reductions due to toxicity. Very, very few patients actually had those problems.

Charles Ryan: And as the rPFS Kaplan-Meier Curves will attest, there were a proportion of patients who, even though they were receiving lutetium, did have relatively early progression and the curves notably began to separate after about three months' time, which might be that imaging time point, the first analysis time point.

Oliver Sartor: Actually, good point. And that is what I was alluding to, Chuck. If you look at that first imaging time point, about 20% of the patients were already having image progression. So, unfortunately, it doesn't work for everybody and we need to learn more about the patients that it doesn't work in as well as about the patients who really are way out on that K-M curve and have a huge benefit. As with any phase three, there is a fair amount of heterogeneity.

Charles Ryan: Right. When we look at PSA responses, which is a little bit problematic to call PSA responses in a PSMA targeted therapy because you could of course see how they might be together in terms of PSA response being more likely to be seen in high PSMA expressing tumors, but it's about a 50% PSA response proportion, which is actually quite notable when we think about the prior studies in this clinical state, enzalutamide, abiraterone, and cabazitaxel. All of them had PSA response proportions in the thirties, I believe, in this heavily pretreated patient population.

Oliver Sartor: Yeah. I think the PSA response rate was quite impressive. It was 46% confirmed. I do want to emphasize confirm because there are other studies, I might mention, Australian studies that just looked at the best PSA response. They didn't look at the confirmed PSA response. As we go forth, I think we can use PSA as a potential biomarker for a response here. We of course have more data to look into. Chuck, I still remember when you did the 302 study, how you carefully looked at the relationship between PSA and survival. Those types of studies, which I really admire in your 302 study, have not been done here.

Charles Ryan: Right. And we'll be learning a lot more, I'm sure, about the VISION trial over time, which is a good thing and typical of positive, successful phase three studies. There has been some question about the control arm here and what was used and the efficacy of what was used. And in indeed in the waterfall plots of the PSA responses, if we are going to talk about them, there was only 7% PSA response in the control arm. Let's imagine that lutetium 177 is available for clinicians and they are faced with a choice of lutetium 177 PSMA targeted therapy or some of the other existing standards. How is the clinician to think about what was given in the control arm, what it tells us about the VISION trial, and how other therapies may be sequenced or added to or sequenced with the lutetium?

Oliver Sartor: Great question. What I want to do is back up and talk about these patients in a little more detail. So, all the patients had had prior abi, enza, apalutamide, one of the advanced AR targeted agents. Many of them had two. It turns out everybody had at least one taxane. Many patients had two. 38% of the patients actually had cabazitaxel in addition to docetaxel. So we really are talking about extremely heavily pretreated patients. It was also part of the trial design that if you wanted to have chemotherapy or the clinician thought that you would benefit from chemotherapy, you should go get chemotherapy and not enter into the trial. But if we look in a broad statistical basis, Chuck, one of the things that have been an ongoing concern about chemotherapy in advanced prostate cancer, only about 50% to 60% of people in the United States get chemotherapy before they die. And second-line chemotherapy is only given to about 20% to 25% of patients. That's an approximation. I don't know the exact number.

But the truth is not all patients get two lines of chemotherapy, and 38% of these patients had already had a second line. So what do you offer these patients? It turns out in the thinking, and this is important, the idea was we wanted to have a big, broad tent to be very inclusive of the patients who were coming into the trial. If we had required chemotherapy in the control arm, I believe we would have excluded may be as many as 75% or 80% of the potentially eligible patients. So this big tent approach was very purposeful. Could we have used cabazitaxel in the arm and deleted the prior cabazitaxel-treated patients? We could have. That was not done for a conscious decision. So what could we allow?

Well, we could allow second line hormones [inaudible 00:12:10] glucocorticoids, radiation, bone-targeted agents, bone health agents. But the truth is that these individual patients have already been exposed to almost all the above. Trying to choose a control arm was extremely difficult. And so what we decided to do was let physicians make their choices. Now they could specify their choices, but they can change them as well. I've treated patients, like for instance, abiraterone/dexamethasone, you are probably aware that some patients can respond to abi/dex even though they may have progressed on abi/pred. One of my control group patients had an 18-month response. He is one of those guys way out on the curve. And by the way, we documented a BRCA2. And even though we couldn't do the BRCA2 in the trial, when he progressed, I put him on a PARP inhibitor, and then he's now crossed over.

So these patients, at least certainly in my practice, were treated the absolute best way I knew how to treat them. And I wasn't restricted except for the chemotherapies that were prohibited. Unfortunately, I couldn't use the PARP inhibitors on the trial because they were experimental at the time that the trial started. That's a long answer to a very complex question, but hopefully, I hit the points that you were trying to get me to cover.

Charles Ryan: I think you did. And actually, I would point out to critics of this data that the rPFS curve and the OS curve will probably stand up to whatever sensitivity analysis is done. In other words, you just pointed out in your answer, well, if we had restricted the prior cabazitaxel, or this or that, or mandated it, we might have seen a different result. But the likelihood is based on a hazard ratio of 0.43 for rPFS, that any change you could make is probably not going to diminish that outcome.

But I also want us to take a look forward and imagine that we have lutetium available and how clinicians should think about it. I think that was the root of the question, which is should clinicians be thinking of lutetium as third-line therapy, as a fourth-line therapy, if we are getting down that path now? Or where they would use the VISION trial to sequence it for their patients. And finally, I should point out that this study was done in nine countries, the US and Canada, and many sites in Europe and Australia. And so in some of those places, the other therapies were somewhat of limited availability for the patients.

Oliver Sartor: Good point, Chuck. The trial was designed to be a third or fourth-line trial, but in some cases, it is actually the fifth-line, abi, enza, docetaxel, cabazitaxel, then entry into the trial for some of the patients. Although you could have come on with, let's say, just abi and docetaxel and then gone on. But I think it will be firmly in the kind of third-line space with a little bit of fourth-line use.

As it turns out, I actually believe that when alternatives are given for second-line chemotherapy of this particular agent, I think for those who are eligible, that they will be choosing the radioisotope. The side effect profile is really good. The PSA response rate is really good. We didn't talk about objective response rate, but the objective response rate in tumor shrinkage was actually over 50%, 9% on the CRs, and about 41%-42% on the PRs. This is a highly active agent in the selected population. I do want to emphasize, we probably could do better. We're probably going to learn more about the ideal patient. Right now, we have a positive phase three. And as you pointed out, and as you've experienced in your own career, having a big positive phase three gets a lot of excitement, and then oh so many questions arise thereafter so we can optimize the treatments for all of our patients.

Charles Ryan: Right. It's not the end of the story. It's not the beginning of the story. Perhaps it's the end of the beginning of the lutetium story though and we will begin to get to a little bit of a deeper understanding.

Oliver Sartor: Well said. I like that. I think I'm going to raise that issue, but I'll give you the attribution.

Charles Ryan: I think it was Churchill, perhaps.

Oliver Sartor: I think it was Churchill that talked about the end of the beginning. [crosstalk 00:16:29].

Charles Ryan: Let's go a little bit deeper on safety here. First of all, it was found to be generally safe. There is some marrow toxicity, and salivary gland toxicity has been identified. That's pretty well known. I guess what I would ask you is, imagine this is out there and clinicians are thinking about using this for a patient, is there a patient who is ideal for this treatment based on the VISION trial in terms of symptoms or disease burden? And is there a patient who is perhaps not going to benefit or for whom this should not be the choice?

Oliver Sartor: Well, first of all, I think that from other studies that the degree of PSMA positivity may in fact be predictive of outcome. Now, I can't say it on the basis of the VISION trial, [inaudible 00:17:16].  But the patient with some nice hot high SUV, PSMA positive mets with nothing outside of the PSMA positive range, I think that is a really good candidate.

What areas were concerning to me? Well, the area that actually concerned me more than others was liver mets. So the overall survival, now remember it's only a subset, and it's about 12% that had liver mets, but the overall survival hazard ratio of those liver mets was about 0.87. That's not quite as good as what I would have hoped for. Could we get responses? Absolutely.

I want to know a little bit more about that subset. So if you're looking at patients, particularly if they have PSMA negative lesions in their liver, I don't think we want to go with that. We do not know a lot about neuroendocrine. Some of these patients will have had some neuroendocrine type phenotype. We didn't really study that. We weren't compulsive about excluding or compulsive about including. These were just post abi, enza, post taxane, PSMA positive patients. But I will say that those individuals who developed neuroendocrine or have a small cell component of their disease, are probably not the patients we want to treat.

Charles Ryan: Yeah. You should point out. I mean, the liver metastasis population was a pretty small proportion of the overall study and the [crosstalk 00:18:36] did cross one.

Oliver Sartor: It was.

Charles Ryan: So I wouldn't say that you can say definitively that it's... It is a worrisome group as you point out. I agree with that. It's not, I think, data to suggest that we should not go with patients with liver metastasis. Just that we probably need to maybe do a little bit [crosstalk 00:18:53].

Oliver Sartor: Yeah. No, no. Chuck, I agree. I guess maybe I was... I'm trying to be critical to data and it's 12% of the population-wide confidence intervals. The point estimate on the hazard ratio was 0.87 for survival. So that was a cautionary point. I wouldn't say no if I had a patient who had liver mets, PSMA positive, met the criteria of the trial. Absolutely. I would try.

Charles Ryan: Yeah. Finally, what's interesting is I think this is a radiopharmaceutical, we have a radiopharmaceutical available to us. radium-223. Lots of differences, of course, between these two therapies. Radium-223 really entered the market as a treatment for people with bone pain and disease-related pain. As I'm looking through the VISION data, I'm not seeing data on pain, palliative improvements, or baseline pain. Do we have that data? And what would we advise clinicians on the use of lutetium in a symptomatic patient population?

Oliver Sartor: So it's in the New England Journal, to be able to look at health-related quality of life, and we very specifically looked at the deterioration in the quality of life over time, Kaplan-Meier estimates. Unequivocal, better preservation of quality of life in those treated with a PSMA lutetium. I was going to say more data to follow if you will. So I'm not fully at liberty to discuss that unpublished data, but I think you will be pleased when you have the opportunity to see it.

Charles Ryan: Okay. Well, I'm just glad to hear that that analysis is ongoing because I think that was something that will come up in the clinic. So speaking of the clinic, this is not an FDA-approved therapy for mCRPC at this time, as we record this in June of 2021. Is there an opportunity for a patient in the US or elsewhere to get this treatment on or off a clinical trial or expanded access program?

Oliver Sartor: Yeah. There are two ways to do it. There is an expanded access program. We do have it open at Tulane, and I almost hate to say that we are almost overwhelmed right now with referrals, which quite frankly are coming in from all over the US because word has gotten out. We do have it open. We're trying to keep up. We are having a little bit of a hard time keeping up right now, but you can also do a single patient Investigational New Drug (IND). I'm sorry. I do not know exactly where the expanded access sites are. And that's an important question, but I don't know the answer to it. So forgive me.

Charles Ryan: I'm sure that information is retrievable somehow. Well, thank you, Oliver, for this really in-depth conversation about the VISION trial, which I think will emerge as one of the pivotal studies in our field over time. Still a lot of questions about how we will optimize the utility of this therapy in the clinic and when it becomes available, but a really great effort here in bringing together a randomized phase three trial that's likely to change the standard of care. Thank you so much for joining me.

Oliver Sartor: Thank you, Chuck. Really a pleasure to be able to discuss it today.