The Promising Path of PSMA PET Imaging and Lutetium-177-PSMA in GU Oncology and Prostate Cancer Treatment - Susan Slovin

November 9, 2022

In this discussion, Susan Slovin and Alicia Morgans discuss the incorporation of PSMA PET imaging and emerging treatments like lutetium-177-PSMA in genitourinary oncology. Referencing ASCO 2022 talks and clinical trials, particularly Dr. Mike Hofman's study comparing lutetium-PSMA and cabazitaxel post-docetaxel, they review three-year data showing no significant difference in overall survival between the treatments despite initial data favoring lutetium. Dr. Slovin raises concerns about the need for long-term side-effect data, trial enrollment confusion, and issues around availability and cost. Challenges including patient selection, access, and real-world applicability of lutetium, especially for patients in visceral crisis, are explored. They emphasize the importance of appropriate treatment choices and overcoming access issues, mentioning studies like TheraP and VISION. The conversation emphasizes the need for improved eligibility criteria, insurance coverage, and training in interpreting PSMA images, and the significance of ongoing genomic profiling.


Susan Slovin, MD, PhD, Medical Oncologist, Associate Vice Chair, Academic Administration, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Susan Slovin from Memorial Sloan Kettering Cancer Center, where she is really reviewing the eloquently-balanced talk that she gave at ASCO 2022 related to lutetium and PSMA imaging and end treatment at that meeting. Thank you so much for being here, Dr. Slovin.

Susan Slovin: Thank you, Dr. Morgans. It's always a pleasure to see you and to have our very timely discussions regarding some of the late breaking abstracts and some of the new things that are out there in the world of GU oncology. I was very excited to do a commentary after the presentations at ASCO, because they all pivot around two central points. One is, the integration of PSMA PET imaging into active care of our patients. And the second is, how do we integrate some of the newer treatments that are now coming out, in particular lutetium-177-PSMA. Our own experience in having developed, or co-developed, a lot of these technologies has been very exciting, but I think that there's still some issues that we have to face. So, what I would like to do is really give you my own gestalt of what's been interesting about each of these abstracts.

Mike Hofman, as many of you know, is a radiation oncologist from Australia, and he's been very pivotal in leading a clinical trial. And again, these slides are available at the ASCO website. But, what I think was very interesting is that he presented 3-year data on lutetium PSMA that was randomized against patients who were getting cabazitaxel. So this was very interesting, because we have a new standard of care. Cabazitaxel as you know, is a second-line treatment post-docetaxel, but it was interesting that, if you failed docetaxel, should you be giving lutetium PSMA or should you be giving cabazitaxel? Is there a benefit? Is there a superiority? And although the clinical trial was really not looking at superiority or an inferior aspect of either drug, it did bring to light several important features.

As many as you know, the randomization had been gallium for a total of up to 6 cycles versus cabazitaxel up to 10 cycles of treatment. The long-term data was looking at post-protocol, systemic treatments. How many of them went on to other drugs such as even abiraterone, enzalutamide if they hadn't had it before? And if you had cabazitaxel did you go on to lutetium subsequently? It was a very straightforward trial and at, I think it was ASCO maybe 2 years ago, there had been some updates looking at progression-free survival, both radiographic and overall survival. And what was very tantalizing at that time is that, in favor of the lutetium arm, there was an 8.7 month versus a 3.4 month median radiographic progression-free survival in favor of the lutetium arm. And when you looked at overall survival, again, very tantalizing, 15.3 versus about, I guess it was 11.3 or 11.5 months, again, in favor. So I think this got everybody's, pardon the expression, all a-twitter that this is really a very novel and very exciting treatment in favor of lutetium.

When you looked at the subsequent overall survival now at the 3-year analysis, what was very surprising, and again, this is the intent-to-treat population, there actually was no difference at all between either arm, whether it's lutetium or cabazitaxel. So both at 19.1 versus 19.6 months. There was no level of significance, and I think that was a little surprising for most people. There were no additional safety signals. We did know their PSMA positivity, and in those patients who went on trial, they had to have had SUVs that were certainly greater than 10 to indicate high avidity. But the presence of PSMA activity on PSMA PET scan, whether you were going onto the cabazitaxel arm or the lutetium arm, did not seem to really change your response, but there was some suggestion that if you had a PSMA SUV mean of greater than 10, your overall survival was roughly 12 months, versus if it was less than 10 where you had a 2 month. So, interesting to use PSMA as a predictive model.

Dr. Hofman actually made my life very easy when I was on the podium, because the strengths is that this was a prospective, randomized, multi-centered trial, there were a 3-year follow up. This was not powered to be an inferiority or a superiority test, but there were limitations. There were some post-protocol treatments that seemed to confound the overall survival. A lot of patients who were randomized to the cabazitaxel, or quote-unquote standard of care arm very often left the trial very precipitously because they wanted the active treatment arm. So you had those patients who were randomized not to their favorite arm and went off the trial and got enrolled on the same trial, but at a different facility. Initially, this really confounded the trial, the trial was on hold because of this duplicative enrollment, which actually initially skewed the data.

The overall survival actually as an endpoint, even as it was a secondary endpoint, because actually the first primary endpoint, which I should have mentioned before, was a PSA 50, the ability to drop the PSA by greater than 50%, which they did accomplish, it's just, there was no overall survival benefit. And the fact of the matter is, do we know long-term side effects? The answer is, no, we don't. We know at 3 years, safety is very reasonable. We do know that patients are now living greater than 10 years. So, I think it's very reasonable to have expectations that within the next 5 to 10 years, we will see something that may or may not be a safety signal.

The takeaway, for example is, how do we strategize where to put this drug? Do we do it right after docetaxel? Do we do it after cabazitaxel in the second-line or third-line setting? We really don't know. And as I think you and I have discussed, it's sort of very reminiscent of the old days when enzalutamide and abiraterone came out, because we never knew, how do you strategize them? Which do you give first? The mechanism of actions are very different, but they all do the same thing. They modulate the androgen receptor. So, this is still something that we don't know.

And then of course, there's the real-world usage. You need to have a radiation facility, you need to have a clear medicine facility, people have to have coverage for both the PSMA scan, and then of course, lastly, and I think very, very importantly for all of us, whether you're in Europe or here, is the availability and how to use the PSMA imaging. Remember that the package insert says that the patients who go on lutetium have to have had docetaxel first and then have to have gallium PSMA imaging in order to be eligible for the study. And again, if you don't have a gallium facility, what do you do? So if everybody looks at one of the footnotes of the NCCN guidelines, you will actually see that you can, based on consensus have either gallium or PyL as the appropriate PSMA imaging modalities.

Now, we kept pivoting between the PSMA imaging and lutetium, and I think what's very interesting is trying to determine whether prior or concomitant treatment subgroup analyses have any role in selecting patients. And Dr. Vaishampayan from Wayne State University did a very nice little review, and I'm just going to very briefly tell you that the takeaway was that patients who received either one versus two or greater taxanes, for example, actually had overall survivals of 3 months difference. So, if you had one or more taxanes prior to getting lutetium, they found that there was definitely a benefit, that was 16.2 versus about 13.6 months. If you had androgen receptor signaling inhibitors, one or more, again, there seemed to be a benefit in terms of survival, but there really were very small differences in outcomes in terms of the subgroups. So, essentially, this was hypothesis generating. So whether you had radium or Zometa or one or more chemotherapies or one or more androgen receptors signaling inhibitors, frankly, it didn't seem to make a difference.

Then lastly, how can we really look at response criteria? And you and I both know that when we're doing a lot of imaging evaluations, what is really a response? Is it a decline in PSAs? If you're using PSMA-guided imaging, is it a decline in SUV? Is it looking at SUVmax? Is it a difference between the high and low and median? Andy Armstrong presented a very interesting way of trying to integrate response criteria when we use PSMA imaging. And so, he actually looked at the gallium PSMA-11 PET imaging and tried to justify it as a prognostic tool for looking at clinical outcomes for patients who received the lutetium PSMA.

He looked at the data from the VISION study. He looked at a variety of different PSMA PET parameters. I'm just looking here so I don't miss any of them, but the SUVmean, the SUVmax, tumor volume, tumor load, the presence of a PSMA-avid lesion based on regions. And so, he just did a segmental anatomic region analysis looking at either the whole body or by region or just looking at very specific regions, the GI area or the pelvic area, and seeing if he could make any difference. And so, among men who were treated with the lutetium-177 and they had PSMA-avid disease on their PET scan, they found that a higher whole-body SUVmean seemed to correlate more with improved long-term clinical outcomes.

Now, the nuclear medicine doctors are really on top of this, there's been the PERSIST and several other papers that have been published looking at various criteria. I don't know that this has all been well-integrated and whether or not we really have any one recommendation on how to really evaluate it. I think this is very refreshing in the sense that they were able to identify, in particular, what they felt was a quartile, as opposed to any other numerical evaluation. But the highest SUVmean per quartile seemed to have a radiographic progression-free survival benefit of 14 months, and if you look at the overall survival using that same criteria, about 21.4 months. And that's versus 5.8 versus 14 months in the lower quartile. That seemed to correlate as well with improved objective and PSA responses.

So, again, more information that is going to help us learn how to integrate all these imagings and radiographic changes into our practice. I think all three abstracts, and we can talk about that, really underscore the need to refine and actually stratify eligibility criteria. And, we're still on a learning curve. I think our biggest problem right now is availability, cost, particularly with insurance coverage, and interpretation. I don't think the average nuclear medicine doctor, when he or she gets the nuclear medicine PSMA images will be ready to evaluate. I think there will require a fair amount of training.

I know I've done a lot of talking here, but I'd be glad to hear your thoughts about how you're using it and how you think this is really going to impact our treatment. We always have something new and, of course, there is a learning curve. Thank you for having me discuss all this.

Alicia Morgans: Absolutely, and thank you for laying all that out. So, TheraP and then two post-hoc analyses of VISION. Really, really, really important and interesting as we think about lutetium-PSMA-617. Just to start with the TheraP study, one thing that I think is important for us to recognize is that we must remember that these patients were very carefully selected using both a PSMA PET and an FDG PET to really identify the patients that they thought would be the best responders to lutetium as a therapy. And I think that's important as we think about applying this treatment decision making algorithm, because there are going to be a number of patients who are actually were not included in TheraP, and so they would not be even considered in this head-to-head comparison.

Additionally, as you said, there are real-world challenges to getting lutetium in a timely basis and there are access issues based on, of course, having to get a PSMA PET and then also having to travel to a place that's actually delivering lutetium, which has been in short supply due to manufacturing issues, though I think that is starting to improve at this point. So, what are your thoughts just in terms of day-to-day clinical practice? If you have a patient who has visceral crisis, for example, are you going to still reach for lutetium? Do you feel like that may be the patient you want to reach for cabazitaxel just due to timing and the known effects of chemotherapy in that setting? Because there are barriers, and of course, TheraP did not include an all-comers population.

Susan Slovin: The TheraP definitely had a bias, which are those patients who had the SUVs certainly greater than 10. And of course, we don't know. That's their arbitrary cutoff, but is there a subset of patients who may have very low expression, but still could respond. And that's part of the stratification. Somebody in visceral crisis, liver disease, lung disease, I would not rush to lutetium. I would be on second-line chemotherapy, to be honest with you, it may be a platinum compound, carboplatin, but I would be very nervous about doing lutetium.

I don't think there's enough information about it, and quite frankly, how many cycles would you use? I'm not saying that lutetium might not work, but I need something tried and true at that moment, and having to wait for somebody to have the drug ready for them, having them screened, that's a lot to ask of a patient who's ill, and I think that's a major deterrent. Remember, you need a facility to make the drug. And if you're in the community, I can't see, unless you're transferring somebody to a center of excellence, so to speak, I think the availability will be delayed and patients may be in crisis a little bit longer than you would feel comfortable doing.

And, I think it is a comfort zone for a lot of the doctors. We're getting a lot of calls. Everybody wants lutetium the patients are contacting us, and they don't realize that they need eligibility. They just can't walk on. What do you do with somebody who's non-PSMA-avid? Is there a possibility that, in spite of the PSA negativity, they could respond? We just don't know, and that's going to be another subgroup, I think, that's going to have to be interrogated at some point.

Alicia Morgans: Thank you for that. I do think that these are issues that we're going to continue to improve upon, and we are, hopefully, going to get more data. But there is this misconception, I think about, as you said, by the patients, at least, that you just walk in the door, you have to just see the right doctor, and then you can get the drug. And it is a drug that is highly effective and TheraP shows us that. But I do think it's important for us to remember that we do, thankfully, have actually options, and so choosing the right option with the patient is still going to remain important. And as we move forward, I'm really eager to have us overcome some of these access issues. I'm sure we can, it will just take time and we're in process and we'll get there.

Just to focus on the two other studies that you mentioned, I think it's interesting, this post-hoc analysis of the VISION data that you mentioned presented by Dr. Vaishampayan that really reviewed prior therapies, concurrent therapies, and the impact. It did seem there was a consistent improvement in outcomes with treatment with lutetium as compared to best standard of care only. And so that's encouraging. But also, I think encouraging that prior exposure to radium didn't impair the ability to benefit, or prior exposure or concurrent exposure to other agents, but particularly radium. I think of both radium and lutetium as being options in our armamentarium and I want to keep all the options that I can. Can you comment on this?

Susan Slovin: I wish I had an answer here because this keeps coming up, even with the docs who are first-line in the community. There's no question that radium has been approved for, essentially, palliation of treatment of symptoms. And we are facing a particular crisis here, I think, in terms of, we have all these great drugs, now where is radium going to fit in on the scheme?

Now, I have to tell you, I've seen two patients recently from the community, one of whom transferred his care to an academic center, and I was actually very surprised that in the first-line setting after being started on androgen receptor signaling inhibitor and ADT in the presence of metastatic bone lesions, high-volume disease, that the patient was told that after being on treatment 4 weeks, he would then go on to receive radium-223. Two people now. Very, very shocked that anybody would be bringing this into the de novo metastatic setting when that's not the indication for it, and frankly, neither patient really had pain. So I don't understand why somebody would be doing that and I think there has to be a little bit of more regulatory caution here in terms of the use of these drugs.

Now, it seems that if you've had prior radium, zoledronic acid, androgen receptor signaling inhibitors, that's all very well and good. You're going to respond. But now the question is, how do we, again, strategize where to put any of these. I don't know that a lot of docs are going to be very comfortable with giving 6 cycles of lutetium, patient may have disease recurrence or may not, but they may want to say, "Okay, maybe we'll use radium as a maintenance therapy." I just don't know what the long-term effects are going to be, irrespective of people sometimes saying, "Well, patients are not going to live that long anyway." That's not true.

We have made a major impact on the longevity of our patients, just by the way we've been strategizing our own gut feelings of the biology of the cancer. And I think in spite of the treatment algorithms that may or may not be available to us, we still need to do biopsies, we still need to do genomic profiling to really understand what changes over time, both pre and post each of these therapies.

So, to answer your question, I don't know. I don't know how we're going to figure this out, other than your own gestalt of the patient's marrow reserves, their clinical presentation, and the like. Does that mean that radium is going to fall to the wayside? There's a good possibility that it may not be used. Just like sipuleucel-T, everybody jumped on the bandwagon, and then again, it too has not been used maximally.

Alicia Morgans: Yeah. Well, thank you for that. And then just to address the last abstract, I think it was really interesting Dr. Armstrong's presentation of this SUVmean, that highest quartile, which was actually pretty consistently around a greater than 10, which was interesting because, of course, that's what was identified in TheraP as potentially being predictive of a better response.

Susan Slovin: That's right.

Alicia Morgans: It's really interesting. This is not something, though, that we calculate or that nuclear medicine doctors calculate as they're reading PSMA PETs at this time, this SUVmean. So, where do you see that coming into play? Because at this point, that's really just a trial sort of analysis.

Susan Slovin: Exactly right. The nuclear medicine people have really been on top of everything, and (INAUDIBLE), who has published, very extensively, looking at what they call the PROMIS trial, which was prostate cancer molecular imaging standardized evaluation, i.e. PROMIS, tried to put in a variety of different thresholds of how one would evaluate uptake. He has also come up with a variety of nomograms to determine who really would benefit from going on these therapies based on the uptake on imaging. So, this is giving us, I think, some insight that maybe we can, in a more consistent manner, really provide a guide to who might maximally benefit. Again, this is going to be a learning curve. I don't know that this is a fait accompli in terms of the right way to do it. I think it's one of many different interpretations.

In some of the work that I do with CAR T cells, and we've seen some very interesting responses on PSMA imaging, we saw almost a complete resolution of disease post-treatment, but the question was, how do you represent that? Do you now look, based on this data, SUVmean? Should you be just looking at differences? Do you look at one lesion? And how do you interpret all the lesions? Now, Dr. Armstrong showed by region. But, what if there is no major region? Maybe it's very diffused bone disease and nothing viscerally, how do you interpret it? And I don't know that anybody really knows at the present time. So all I can say is, stay tuned and let's hope that in our collaborations with the nuclear medicine and radiology colleagues, that we can come to some understanding on how to best report the data.

Alicia Morgans: Well, I think that's a great final message, though. Stay tuned, because there is a lot for us to stay tuned to, whether it's understanding how to best sequence, all of these really effective and useful options, whether it is really predicting which treatment may be best for our patients. I think we have a lot to learn, but at the end of the day, it's actually all benefiting our patients because we have more options. And as we really ramp up our ability to give them in a timely fashion and give them to as many patients as possible, I think we will be winning. So, thank you so much for your expertise and taking the time today.

Susan Slovin: Thanks so much, Alyssa, always a pleasure. Take good care.