Praful Ravi: Yes, Phil. So when I see patients with metastatic CRPC, or castrate-resistant prostate cancer, I think of three therapy buckets. I think of the ARPI, or the hormone therapies, or the hormone pills, I think of the chemotherapy bucket, I think of the radiopharmaceutical bucket, and then potentially a fourth bucket in certain populations, the PARP inhibitors. So coming to each of those, the hormone therapy bucket is the ARPIs, which abiraterone and enzalutamide principally, which have the evidence for use in metastatic CRPC, but you've also got apalutamide and darolutamide, which have evidence for non-metastatic CRPC. And these are good drugs. Typically, we're using them earlier in the hormone-sensitive setting now, so the efficacy of these after you've had one of them before is limited, so that's something to bear in mind. In terms of the second bucket, the chemotherapy bucket, these are really the taxanes. I feel like they're the workhorses really here. There's docetaxel and cabazitaxel, both of which have very good evidence for their use. Docetaxel has good evidence for first-line CRPC. Cabazitaxel has proven activity after docetaxel, so you can use them sequentially. In terms of the third bucket, you've got the radiopharmaceuticals, and I'll mention radium here principally before we talk about Pluvicto later on. So radium is a very good drug, has a survival benefit, but only in men with bone-predominant or really bone-only CRPC. It doesn't really work if you've got significant nodal disease, or certainly any visceral disease, because it's a calcimimetic, it just goes to the bone.
And recently, we have a little bit of data for a combination with enzalutamide and radium in CRPC, showing a proven benefit compared to enzalutamide alone, again, in bone-predominant disease. And lastly, in terms of the extra bucket, this is I think about the PARP inhibitors here, olaparib particularly, which are approved in men with homologous recombination repair-deficient CRPC, particularly the BRCA-mutated patients. These men derive significant benefit potentially from drugs like olaparib.
Philip Kantoff: That's a great overview, Praful. Thank you so much. So let's dive right into it with radiopharmaceuticals, and let's begin talking about Pluvicto, the existing and emerging role of Pluvicto in advanced prostate cancer. So we have three large randomized studies that inform us about Pluvicto. First was the VISION study several years ago, then PSMAfore a couple of years ago, PSMAfore was using Pluvicto prior to chemotherapy. And then, most recently was the PSMAddition study, which looked at the use of Pluvicto in hormone-sensitive prostate cancer. So these were very informative studies, but I'm curious how these studies have applied in clinical practice, both in academia as well as in the community. So Dustin, why don't we jump in here and just tell us where you are using Pluvicto in the landscape of advanced prostate cancer?
Dustin Boothe: Yeah, absolutely. When we started our program in 2022, obviously we were using the FDA-approved indication in the post-chemotherapy setting in patients with mCRPC, and these are patients that were heavily-pretreated, and often these patients were waiting for quite some time for that drug, so they had seen everything, and these were sick patients, and that's where we started. And as we gained more experience, the supply became more robust, we started seeing patients that were just immediately after one line of chemotherapy, docetaxel often. And then, with the PSMAfore data, that's when we're now very commonly treating patients in the pre-chemotherapy setting, in the upfront mCRPC setting. And so, that's where we're treating patients, both in the post-chemo and pre-chemotherapy setting. There's some decision points that we undergo as a team. We have a tumor board that we review almost every case in our system, where we decide whether or not this patient is good for Pluvicto upfront versus chemotherapy or PARP inhibitor, and going down those treatment paradigms that Dr. Ravi discussed. But we're seeing good impact and good effects in our patients in that setting. We have not yet applied the PSMAddition data into community practice. I think we're waiting for the FDA approval of that. But excited about the data and excited about the opportunity to apply it in patients where it makes sense.
Philip Kantoff: So let's dive a little deeper into that, Dustin, and just how do you make decisions about whether to give Pluvicto prior to chemotherapy versus after chemotherapy?
Dustin Boothe: Yeah. And this is where, as a radiation oncologist in the systemic therapy setting, I spend a lot of time talking to medical oncologists, and we have a really robust multidisciplinary team. I've learned a lot from Dr. Gill, Dr. Samuelson, some of these excellent medical oncologists that I work with here. And so, like I said, we present all these patients at a tumor board. Patients that have high-volume disease, younger patients, de-differentiated feel, patients who have visceral disease are often going on chemotherapy first. Obviously, we're using NGS to help patients to decide whether or not they're going to get a PARP inhibitor, whether or not that's appropriate. But beyond that, when we're looking at individual patients, we look at all their PET CTs and we look at their SUV values, making sure they meet the criteria for the trial. I think in the community, that's really important, making sure you understand that the PSMA avidity has to be above the liver pool. But also, looking at those radiographic biomarkers and trying to say, "Okay, this is a really good candidate. We have good SUV values, we've got minimal heterogeneity." And then, we also look at it in terms of where can we use external beam radiotherapy. Some of these patients may be a candidate for treating it in an oligo-progressive paradigm. And so, we really try to look at it holistically. But really, the right candidates for Pluvicto in that setting are patients that meet the trial criteria, both radiographically and clinically, and they don't fit that paradigm of needing chemotherapy or PARP inhibitors based on the things we've discussed.
Philip Kantoff: Thanks, Dustin. So Praful, I'm going to move over to you and ask a similar question. What are the clinical and biomarker-based factors that help you make decisions about when to use and where to use Pluvicto?
Praful Ravi: Yeah. I mean, I think Dustin gave a great response to that. I think I echo all those sentiments. I mean, when we think about pre-chemo CRPC, I usually think about, as Dustin was saying, the patient characteristics. Do they have visceral disease? That's a big differentiator. The PSMAfore data was 3% visceral mets, and we had a trial, the PLUDO trial, which was Pluvicto versus docetaxel run by the Canadian group, which was randomizing between lutetium and docetaxel, followed by crossover to the other, and that actually showed maybe a signal towards better outcomes in the docetaxel-first patients that had 22% visceral mets. So again, you get the idea that the patients with especially liver mets, I almost always opt for chemotherapy first. We have reasonable retrospective data saying that these patients respond poorly to Pluvicto. You also think about things like AVPC, aggressive variant genomics, two out of three are p53, PTEN, RB, those are patients, again, probably less likely to respond to Pluvicto. We have some good retrospective data for that as well. And again, a chemotherapy taxane, maybe even taxane-carboplatin doublet could be used there.
And again, as Dustin was saying, in terms of biomarkers, unfortunately, we have limited biomarkers really right now. The best biomarker we have is probably the PET scan. If that PET scan is very avid, high SUV means, again, those patients are more likely to respond. We saw that in the TheraP trial, which was Pluvicto versus cabazitaxel, the SUV mean, 10 and above, was really prognostic and also predictive of benefit to Pluvicto compared to cabazitaxel. So it's those types of things, look at the scan, look at the disease, look at the patient. Some patients are not candidates for chemotherapy. Perhaps they're very frail, they have a history of neuropathy, where docetaxel may be difficult. So those are the things you look at. But there really is an unmet need to develop better biomarkers here to identify who's the patient who's most likely to respond, let's say, to Pluvicto versus something else.
Philip Kantoff: Yeah. I'm interested in that PLUDO study that you brought up, which was a bit of a head-scratcher, I think. But Dustin, what were your feelings about... This is a randomized study of sequencing chemotherapy after Pluvicto, or vice versa, and it turned out that it looks like giving chemotherapy first generated better outcomes. Dustin, how does that play into your decision-making?
Dustin Boothe: Yeah. I mean, I think Dr. Ravi brings up a great point, in that there was, if you compare the amount of visceral disease in that study versus the PSMAfore, that could likely explain that. We've certainly seen that in our clinical experience, that particularly when you have minimal avidity in visible disease, those patients just don't do well, they just don't. But I think what it brings up to me is that we have yet to really understand who responds well holistically, taking into context radiographic biomarkers, as well as genomic and others, to predict who's going to respond well to chemotherapy. We've got a lot of prognostic indicators, but we don't have good predictive that is really going to say patients are going to respond well to radiopharmaceutical versus chemotherapy. To me, it does support some of my practice patterns. At the same time, it raises more questions. And we need to get better at patient selection and understanding who's going to respond better, because the outcomes are good in these studies, but they could be better with radiopharmaceutical therapy, and I think that's where, I think, there's some exciting advances that are going to be happening.
Philip Kantoff: So along the same lines, this patient selection issue, Praful, are there patients who you would not treat with Pluvicto based on PET scans or clinical factors?
Praful Ravi: I think it's important to stress that I always tell patients it's not usually a case of A or B, it's either A followed by B or B followed by A. So yes, certainly there are patients, for example, with very limited SUV avidity in terms of the PSMA PET. As Dustin was saying, we review all our patients with a tumor board, with nuclear medicine. There's limited avidity, they tell us, "Look, there's not much uptake here. They're not a good candidate really for Pluvicto." So those are patients for sure I'd be opting for something else, chemotherapy or something else. The visceral mets is a difficult one, because sometimes the visceral disease is avid, so you're saying, "Well, let's try this followed by that." But again, aside from that PET scan, there's not much else that you can really say, "Oh, this patient should not get Pluvicto." Because the way the trials were designed, the registrational trials, it was a very easy eligibility. It was at least one avid lesion and no negative disease. Now, in practice, the negative disease criteria, we use that less. So if we've got 80% of the lesions are positive, maybe a couple of lesions are negative, we're still going to treat that patient most likely, either now or later. So it's hard beyond just lack of avidity or lack of sufficient uptake to really say, "This patient shouldn't get a radiopharmaceutical at some point." Maybe not now, but certainly maybe later.
Philip Kantoff: Yep. My last question about Pluvicto before we move on is adherence to the clinical trials of giving six cycles versus taking a patient who is a great responder, let's say, whose PSA goes down to very low levels after a couple of cycles. What are your practice patterns right now about stopping and then restarting later versus just continuing on? I'd be curious to hear about that. And on the flip side, patients who have progressive disease, despite a couple cycles of Pluvicto, do you call it quits on these patients? Why don't we start with you, Dustin?
Dustin Boothe: Yeah. It's a fascinating question. And Louise Emmett obviously is doing amazing work there, has produced some data in that space. Jeremie Calais and UCLA has got his trial, adaptive radiotherapy strategies with Pluvicto. And so, we've looked at that data, and what we've done over time is we've adopted imaging and assessment strategies where we pause after three cycles as a decision point. We almost will never give less than two cycles, and that's, again, based on some of the data and the strategies that have been put forward by some of the thought leaders and our own clinical experience. And so, if somebody is an excellent responder, we'll re-image them, either by SPECT or PET, depending on where they're at, and we'll have a discussion. And to me, it's really hard to look at those images in patients who've had a 90% response, undetectable PSA at times, and see that there is no radiopharmaceutical going to tumor, but it's only going to kidney and salivary glands, and then to justify to continue to give them the drug. And so, we've adopted this strategy to, if somebody's an excellent responder and does not have any uptake on their subsequent imaging because the disease has been treated, to pause, and then we'll continue to follow them with PSA and then reflex to imaging and treat them once there's avid disease that the drug can target.
And so, I think that we still need more data, and I know that we're amassing it in those institutions by those PIs that I mentioned. But to me, this is the exciting part of this paradigm, is we can use these images to make good decisions and to adapt therapy in a hyper-precise way, in a hyper-individual way. So we have adopted those strategies using a combination of SPECT and PET, and again, PSA, also reviewing it as a group and trying to make the best decisions for our patients.
Philip Kantoff: That's great. Thanks, Dustin. Praful, do you have anything to add to that?
Praful Ravi: No, I totally agree. We do SPECT at cycle one and cycle three. But I will say that, unfortunately, at least in the VISION-type population, I can really count on one hand the number of patients who've had such a profound response on PET scan PSA where we've been fortunate to be in that point where we could think about stopping. Particularly a patient maybe who's had a great response, maybe not quite a PSA 100 or PSA 99, but is developing toxicity, maybe dry mouth, certainly take a break, take a few months off, see when the disease progresses and give the last, whatever, two, three cycles remaining, I've done that. And in terms of the point about progression, I think certainly I'm also a believer that everyone probably deserves at least two cycles before you say it's not working, unless there's frank clinical progression going on. And I will say that I don't rely on PSA alone in that point. Let's say even the PSA has risen after two cycles, I always like to get a scan, because unfortunately, we don't have a million options remaining. So if there's relative stability on scans despite PSA progression and there's clinical stability, I would continue to treat. But clearly, if there's radiographic progression, in addition to PSA progression or clinical progression, then I think we'd call it quits there.
Philip Kantoff: It's great to see medical oncologists and radiation oncologists agree on so many things. It's very gratifying. So let's move now to a different scenario. A patient has gotten their first taxane, they've been treated with Pluvicto, whatever order you want to imagine. They're now progressing despite the first taxane and Pluvicto. How do you approach these? What proportion of these patients are getting further therapy? Obviously, they're very sick patients in general. What proportion are getting further therapy? And if you were to treat them, what would be the patterns of care? Praful, why don't we start with you?
Praful Ravi: Yeah. So we looked at this in our institution. Amongst the patients, as Dustin was alluding to earlier, these were the patients who were the first cohort of patients getting Pluvicto, and amongst that, in that first year, year and a half of patients who progressed after Pluvicto, only about 30% got subsequent therapy. Now, probably that number is higher now, probably closer to 50%, maybe 50%, 60%, particularly the post-taxane, post-Pluvicto. And really, the standard of care, I would say, in that patient is cabazitaxel if they've not had it already, if they've got bone-predominant disease, radium, although there's limited data for activity of radium post-lutetium, or a clinical trial. Really, alternative ARPI switch is very unlikely to work. So you're not left with that many other options remaining on the table, unfortunately, at that point.
Philip Kantoff: Dustin, any other thoughts on that?
Dustin Boothe: Yeah. It's a challenging situation, and I agree with Praful and what he said. I think this is where alphas come in, the alpha trials. This is where, as we are opening two of those trials, we're putting patients who have progressed after Pluvicto and chemotherapy onto those trials, because there is some potential benefit, the way that alphas work versus betas. But we do have some limited experience of using radium-223. I've had a couple of patients that have responded. Now, there isn't perfect data to report that approach, but I know that a number of folks are doing that, including ourselves. But it's a tough clinical situation. And this is, to me, as a radiation oncologist, and I know, Praful, this is the world you live in, but to me, as a radiation oncologist, what I love is that opening these trials is that I have an ability to offer a therapy in a clinical trial setting that can potentially impact these patients in a significant way and extend their survival, which is something, as a radiation oncologist, we haven't really done before. And so, to me, this is a space that's challenging, but it's also really worthwhile and exciting to be able to offer that to them as a radiation oncologist, in partnership with our medical oncology colleagues.
Philip Kantoff: Right. I think I echo your optimism about alpha-based therapy, either in very far advanced disease or even in earlier disease. Let's finish up here and just get a sense from both of you where the treatment paradigm in metastatic castration-resistant prostate cancer is going in the future. Dustin, why don't we start with you?
Dustin Boothe: Yeah. I mean, I think Praful has got so many arrows in his quiver. I tend to be a little more myopic in my skillset. But I think focus on radiopharmaceuticals and the options in mCRPC, I think we're going to have a number of targets and a number of radionuclides, and once we have those, I think we're just going to see better impact on our patients and better outcomes with our patients. And so, to me, the way I see the field, mCRPC and my ability to impact it, is I see that radiopharmaceuticals offer a paradigm that's impactful, that's effective in patients, and I think we're just at the tip of the iceberg of what we can offer in terms of drugs that have different impact, either it's through different ligands, radionuclides, or both.
Philip Kantoff: Praful, you want to finish it off?
Praful Ravi: Yeah. I mean, I echo that. I think it's very exciting in terms of not only new trials and targets. You've got, as Dustin was saying, new atoms, new targets beyond just PSMA. You think of other common cell-surface targets, they can be targeted too by radiopharmaceuticals, and increasingly are being done in clinical trials. But also, I think combinations are going to be a big thing potentially. We have data from ENZA-p already with enzalutamide plus lutetium versus enza alone, and that was in a patient population with limited prior ARPI experience or no prior ARPI, but that showed survival benefit with a combination compared to enza alone in patients who are poor risk for enza. So I think combinations and novel drugs emerging, which could easily be combined with radiopharmaceuticals, which have non-overlapping toxicities, potentially even things like chemotherapy potentially. So we can combine the things we already have, the arrows in our quiver, if you like, but also, we've got the new frontier in terms of new atoms and new targets and new indications developing all the time with radiopharmaceuticals.
Philip Kantoff: Well, guys, this has been terrific. I really appreciate your time, your insights as radiation oncologists and medical oncologists. So this has been a great session, and the first of the four sessions that we're going to have. So thank you all very much.
Dustin Boothe: Thank you for having us.