Discussion on Patient Selection for Radioligand Therapy in Prostate Cancer - Oliver Sartor and Daniel Petrylak
September 8, 2025
Neeraj Agarwal speaks with Oliver Sartor and Daniel Petrylak about patient selection strategies for radioligand therapy. With multiple treatment options now available for metastatic castration-resistant prostate cancer, the experts emphasize that patient selection has become both an art and science. Key selection criteria include PSMA PET scan parameters, where SUV mean correlates with treatment outcomes and can guide therapy decisions. Dr. Sartor highlights the importance of genetic testing, noting that BRCA2 mutations might favor PARP inhibitors first, while PTEN loss may predict better lutetium response compared to chemotherapy. Disease location matters significantly, radioligands work well for lymph nodes and bone but poorly for liver metastases. Clinical factors like hemoglobin levels, renal function, and hematological status are crucial considerations. The physicians stress using liver uptake as a reference standard and avoiding radioligand therapy in patients with lesions showing uptake below liver levels. They conclude that early treatment and individualized approaches based on genetics, imaging, and clinical parameters optimize outcomes.
Biographies:
Daniel Petrylak, MD, Professor of Medicine (Medical Oncology) and of Urology, Yale School of Medicine, Smilow Cancer Hospital, New Haven, CT
A. Oliver Sartor, MD, Director, Transformational Prostate Cancer Research Center, East Jefferson General Hospital Cancer Center, Tulane University Cancer Center, New Orleans, LA
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Biographies:
Daniel Petrylak, MD, Professor of Medicine (Medical Oncology) and of Urology, Yale School of Medicine, Smilow Cancer Hospital, New Haven, CT
A. Oliver Sartor, MD, Director, Transformational Prostate Cancer Research Center, East Jefferson General Hospital Cancer Center, Tulane University Cancer Center, New Orleans, LA
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
This webpage is equally supported by AstraZeneca and Bayer Pharmaceuticals. Neither company is involved in content development or review, and the views expressed are those of the physician and/or patient contributors.
Read the Full Video Transcript
Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a professor of medicine at the Huntsman Cancer Institute, University of Utah. I'm honored to have two legends in my field, Dr. Oliver Sartor, Director of GU Oncology and professor in Tulane Cancer Center. And Dr. Dan Petrylak again, the Director of GU Oncology and professor in Yale Cancer Center. Welcome.
Oliver Sartor: Thank you, Neeraj.
Neeraj Agarwal: So, we would like to learn from you both about the patient selection regarding radioligand therapy. We have so far Pluvicto Lutetium-177 in the clinic, but we know a wave is coming. So how are you practicing? How are you selecting these therapies over other options which are available, such as chemotherapy with docetaxel, cabazitaxel, radium, sipuleucel-T? There are many other therapies, fortunately, which are available now. What are you looking at and how you are doing it differently, Dan?
Daniel Petrylak: I think in this era, it's really wonderful that we have a plethora of treatments that we can administer our patients. Think back 20 years ago, we only had docetaxel. Now we have other hormonal agents, we have immune agents such as sip-T, as you mentioned, we have radioligand therapy, we have isotope therapy, we have ADCs coming in the future. We have PARP inhibitors now. So how does the clinician select which treatment to use? And I think some of the interesting data that's been generated out of the VISION trial helps us. So we know that PSMA PET scans are a selective factor for going on that particular study. There was a study that was done that looked at those PSMA PET scans and looked at a variety of different parameters, including the SUV mean in terms of the value of the uptake of the tumor cells of the isotope. And it showed that the SUV mean correlated with radiographic progression-free survival, objective response rate, as well as overall survival. So this is one mechanism that we can use if somebody has a high SUV mean, we could potentially select a patient for radioligand therapy.
Also, what's been shown is that after two cycles, if you look at the PSMA PET scans, if you look at the SPECT scans, and the SPECT scans are important because they show the uptake of the prostate cancer cell for the particular isotope because we know that the lutetium PSMA will emit gamma particles, which can be detected by a gamma camera. So you can actually determine whether a patient is responding by looking at the particular SPECT uptake. And we can use this as a way of saying, well, whether a patient should stop after two treatments, stop after three treatments. We could look at progression as well. So this is a way of selecting and then as well as monitoring the patients who are on lutetium therapy.
Neeraj Agarwal: Thank you, Dan. So, Oliver, you literally got Lutetium-177 into the clinic, so congratulations for the VISION trial and so many other accomplishments. But coming back to literally learning from the horse's mouth, if you will, if you have a patient who is progressing on ARPI, for example, and their SUV mean is important to me, but I know it can vary from two PSMA PET scans, which were done four weeks apart. We have seen discrepancies. And CT scans, results are already there, PSA is there. In your clinic, how are you making the decision to choose a radioligand therapy, for example, there is only Pluvicto right now in the clinic over say docetaxel chemotherapy?
Oliver Sartor: Neeraj, it's a very interesting question and it's a bit of an art form rather than a science right now, and I appreciate what Dan said about the multiplicity of options we have. I do genetic testing, I'm looking for things that might be sensitive to PARP like the BRCA2. And quite frankly, that would be a consideration if I have a BRCA2 mutation, I'm going to probably go with that PARP inhibitor first. I'm thinking about the location of the disease. One of the things we found out about the radioligands is that they're pretty good for lymph nodes and bone, but really not very good for liver. Now, we all know that liver is a bad prognostic sign across the board, but if you've got a relatively low SUV uptake on a lesion in the liver, that patient is not going to be doing very well unless you treat the liver lesion independently.
When we're looking at the SUVs, there are a couple of things that are interesting. The PSA response is predicted very, very well by the SUV mean or SUV max by the way. But when we ran a whole series of multifactorial analyses, we began to see that other parameters, the things we're very familiar with, also have a very, very important role. Hemoglobin for instance. When the hemoglobin is good, the response is typically good and the patients live a long time. LDH, lymphopenia, things we're familiar with. We actually did a multivariate analysis with and without the PSMA PET scan. And you know what? It wasn't that much different when we put in all the clinical variables. We're also looking at these different genetics. There are certain things that are bad and if we look at a comparison study, and this is a very interesting study done between cabazitaxel and the PSMA-617 lutetium, it's called the TheraP trial and it was run in Australia.
So here we have chemo head-to-head with lutetium. First of all, overall survival, no different. PSA response rate, better with lutetium. But there were some things that were interesting and made a distinction between the two arms. If you had a PTEN loss, you did better if you got lutetium than cabazitaxel. But if you had AR amplification or an AR ligand-binding alteration kind of taken in totality, you actually did better with cabazitaxel. So there's some interesting things out there that go beyond the PSMA PET scan. That's kind of my message.
Neeraj Agarwal: I have my colleagues from the community who have asked me this question. Do you have any patients you would not prefer radioligand therapy up front over chemotherapy?
Daniel Petrylak: Well, I think you look at the parameters for entry into the study for VISION. Firstly, renal function. A patient who has poor renal function may not be the right candidate for radioligand therapy. And I don't believe there've been studies that have looked at dose adjustment, which is something we really do need to look at in terms of whether it's safe to give this with patients with inadequate renal function.
Inadequate hematological function, somebody who may be in DIC, low platelet counts. We're seeing more of these patients occur. So that's somebody that may not be appropriate for radioligand therapy because we know that there's a hematological effect. Now, the question is can you break them out of DIC by giving them radioligand therapy? Well, that's an important question that needs to be answered, but I think that those two groups, in addition to what Oliver said about the patients with hepatic metastasis, those are the ones that we should tend to go with other treatments in that situation.
Oliver Sartor: Let me cover one of the criteria, just to kind of be clear. When you're running the PSMA PET scan, we use the liver as a reference organ for the uptake. So in order to get on the VISION trial, you had to have metastatic lesions with uptake greater than liver. If you had lesions that were less than liver, particularly lytic bone lesions or hepatic lesions with PSMA PET uptake less than liver, turns out those are not good candidates. UCLA actually did a study where they put in these type of patients into the lutetium study, they did very, very poorly. So you want to look not only for the positive lesions, you want to look at the negative lesions and where they are, very important.
Daniel Petrylak: Exactly. And that's the type of patient that I would put on chemotherapy first-
Oliver Sartor: Absolutely.
Daniel Petrylak: ... in that situation.
Neeraj Agarwal: So any final comment then on patient selection for Pluvicto for now?
Daniel Petrylak: It's interesting that the common theme, and this has been going on for almost 30 years, about hemoglobin being a poor prognostic factor, is seen throughout all of our different clinical trials, and that's something we need to look at in our patients as well. It's something that portends prognosis, perhaps response to treatment as well. So I think that, again, it's important to use next-generation sequencing, it's important to look at the PET scans. It's also important to look at conventional imaging of the liver because sometimes you can miss those on the PET scans as we mentioned before. So it's not just one parameter that you're going to look at in our patients. You have to weigh each one based upon the molecular profiles, based upon the imaging, and also based upon the potential toxicity.
Neeraj Agarwal: So coming back to being a good clinician?
Daniel Petrylak: Absolutely.
Neeraj Agarwal: Oliver?
Oliver Sartor: One thing I didn't mention, but it's a little bit interesting. We have some preliminary data with circulating tumor DNA, the kind of tumor DNA, as being important. And the other thing we did not mention is total tumor volume, and it's prognostic across the board. You got a whole bunch of tumor, you're not going to do very well, and that's regardless of therapies. The clinicians need to weigh in about when to think about the therapies and the context of what other therapies are available. And that should be very individualized based on the genetics, the pace of the disease. There are patients who may have oligometastatic disease, it may need a little SBRT and not much more. There are a whole series of things we need to take into account. It's not just the scan.
Neeraj Agarwal: It's great to have option of Pluvicto in the clinic for our patients with MCR.
Daniel Petrylak: One other point, and again, this is seen in that particular study looking at the PSMA PET scans about the total tumor volume. Earlier treatment is better. Catch the patient early, make sure that you detect disease early. And I think that this is going to be the theme of the future.
Neeraj Agarwal: Yeah, I agree. I mean, even for ARPIs, earlier treatment is panning out to be better than later treatment.
Daniel Petrylak: Can I make one other point?
Oliver Sartor: Mm-hmm.
Daniel Petrylak: Very interesting thing Oliver mentioned about the cabazitaxel data and the AR mutations. So we're actually doing a trial right now with ARV-766, which is a PROTAC that targets the androgen receptor, particularly the androgen receptor mutations. And that's been found to be one of the biggest upregulators of PSMA. So we're going to do lead-in study looking at ARV-766 for approximately two weeks, pre- and post- PSMA PET scans, and then hit them with Lutetium-177. Really excited about this study.
Neeraj Agarwal: That's wonderful. Well, thank you very much for taking the time to share your experience of selection of patients for Pluvicto and other radioligand therapy.
Daniel Petrylak: Thank you.
Oliver Sartor: Thank you, Neeraj.
Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a professor of medicine at the Huntsman Cancer Institute, University of Utah. I'm honored to have two legends in my field, Dr. Oliver Sartor, Director of GU Oncology and professor in Tulane Cancer Center. And Dr. Dan Petrylak again, the Director of GU Oncology and professor in Yale Cancer Center. Welcome.
Oliver Sartor: Thank you, Neeraj.
Neeraj Agarwal: So, we would like to learn from you both about the patient selection regarding radioligand therapy. We have so far Pluvicto Lutetium-177 in the clinic, but we know a wave is coming. So how are you practicing? How are you selecting these therapies over other options which are available, such as chemotherapy with docetaxel, cabazitaxel, radium, sipuleucel-T? There are many other therapies, fortunately, which are available now. What are you looking at and how you are doing it differently, Dan?
Daniel Petrylak: I think in this era, it's really wonderful that we have a plethora of treatments that we can administer our patients. Think back 20 years ago, we only had docetaxel. Now we have other hormonal agents, we have immune agents such as sip-T, as you mentioned, we have radioligand therapy, we have isotope therapy, we have ADCs coming in the future. We have PARP inhibitors now. So how does the clinician select which treatment to use? And I think some of the interesting data that's been generated out of the VISION trial helps us. So we know that PSMA PET scans are a selective factor for going on that particular study. There was a study that was done that looked at those PSMA PET scans and looked at a variety of different parameters, including the SUV mean in terms of the value of the uptake of the tumor cells of the isotope. And it showed that the SUV mean correlated with radiographic progression-free survival, objective response rate, as well as overall survival. So this is one mechanism that we can use if somebody has a high SUV mean, we could potentially select a patient for radioligand therapy.
Also, what's been shown is that after two cycles, if you look at the PSMA PET scans, if you look at the SPECT scans, and the SPECT scans are important because they show the uptake of the prostate cancer cell for the particular isotope because we know that the lutetium PSMA will emit gamma particles, which can be detected by a gamma camera. So you can actually determine whether a patient is responding by looking at the particular SPECT uptake. And we can use this as a way of saying, well, whether a patient should stop after two treatments, stop after three treatments. We could look at progression as well. So this is a way of selecting and then as well as monitoring the patients who are on lutetium therapy.
Neeraj Agarwal: Thank you, Dan. So, Oliver, you literally got Lutetium-177 into the clinic, so congratulations for the VISION trial and so many other accomplishments. But coming back to literally learning from the horse's mouth, if you will, if you have a patient who is progressing on ARPI, for example, and their SUV mean is important to me, but I know it can vary from two PSMA PET scans, which were done four weeks apart. We have seen discrepancies. And CT scans, results are already there, PSA is there. In your clinic, how are you making the decision to choose a radioligand therapy, for example, there is only Pluvicto right now in the clinic over say docetaxel chemotherapy?
Oliver Sartor: Neeraj, it's a very interesting question and it's a bit of an art form rather than a science right now, and I appreciate what Dan said about the multiplicity of options we have. I do genetic testing, I'm looking for things that might be sensitive to PARP like the BRCA2. And quite frankly, that would be a consideration if I have a BRCA2 mutation, I'm going to probably go with that PARP inhibitor first. I'm thinking about the location of the disease. One of the things we found out about the radioligands is that they're pretty good for lymph nodes and bone, but really not very good for liver. Now, we all know that liver is a bad prognostic sign across the board, but if you've got a relatively low SUV uptake on a lesion in the liver, that patient is not going to be doing very well unless you treat the liver lesion independently.
When we're looking at the SUVs, there are a couple of things that are interesting. The PSA response is predicted very, very well by the SUV mean or SUV max by the way. But when we ran a whole series of multifactorial analyses, we began to see that other parameters, the things we're very familiar with, also have a very, very important role. Hemoglobin for instance. When the hemoglobin is good, the response is typically good and the patients live a long time. LDH, lymphopenia, things we're familiar with. We actually did a multivariate analysis with and without the PSMA PET scan. And you know what? It wasn't that much different when we put in all the clinical variables. We're also looking at these different genetics. There are certain things that are bad and if we look at a comparison study, and this is a very interesting study done between cabazitaxel and the PSMA-617 lutetium, it's called the TheraP trial and it was run in Australia.
So here we have chemo head-to-head with lutetium. First of all, overall survival, no different. PSA response rate, better with lutetium. But there were some things that were interesting and made a distinction between the two arms. If you had a PTEN loss, you did better if you got lutetium than cabazitaxel. But if you had AR amplification or an AR ligand-binding alteration kind of taken in totality, you actually did better with cabazitaxel. So there's some interesting things out there that go beyond the PSMA PET scan. That's kind of my message.
Neeraj Agarwal: I have my colleagues from the community who have asked me this question. Do you have any patients you would not prefer radioligand therapy up front over chemotherapy?
Daniel Petrylak: Well, I think you look at the parameters for entry into the study for VISION. Firstly, renal function. A patient who has poor renal function may not be the right candidate for radioligand therapy. And I don't believe there've been studies that have looked at dose adjustment, which is something we really do need to look at in terms of whether it's safe to give this with patients with inadequate renal function.
Inadequate hematological function, somebody who may be in DIC, low platelet counts. We're seeing more of these patients occur. So that's somebody that may not be appropriate for radioligand therapy because we know that there's a hematological effect. Now, the question is can you break them out of DIC by giving them radioligand therapy? Well, that's an important question that needs to be answered, but I think that those two groups, in addition to what Oliver said about the patients with hepatic metastasis, those are the ones that we should tend to go with other treatments in that situation.
Oliver Sartor: Let me cover one of the criteria, just to kind of be clear. When you're running the PSMA PET scan, we use the liver as a reference organ for the uptake. So in order to get on the VISION trial, you had to have metastatic lesions with uptake greater than liver. If you had lesions that were less than liver, particularly lytic bone lesions or hepatic lesions with PSMA PET uptake less than liver, turns out those are not good candidates. UCLA actually did a study where they put in these type of patients into the lutetium study, they did very, very poorly. So you want to look not only for the positive lesions, you want to look at the negative lesions and where they are, very important.
Daniel Petrylak: Exactly. And that's the type of patient that I would put on chemotherapy first-
Oliver Sartor: Absolutely.
Daniel Petrylak: ... in that situation.
Neeraj Agarwal: So any final comment then on patient selection for Pluvicto for now?
Daniel Petrylak: It's interesting that the common theme, and this has been going on for almost 30 years, about hemoglobin being a poor prognostic factor, is seen throughout all of our different clinical trials, and that's something we need to look at in our patients as well. It's something that portends prognosis, perhaps response to treatment as well. So I think that, again, it's important to use next-generation sequencing, it's important to look at the PET scans. It's also important to look at conventional imaging of the liver because sometimes you can miss those on the PET scans as we mentioned before. So it's not just one parameter that you're going to look at in our patients. You have to weigh each one based upon the molecular profiles, based upon the imaging, and also based upon the potential toxicity.
Neeraj Agarwal: So coming back to being a good clinician?
Daniel Petrylak: Absolutely.
Neeraj Agarwal: Oliver?
Oliver Sartor: One thing I didn't mention, but it's a little bit interesting. We have some preliminary data with circulating tumor DNA, the kind of tumor DNA, as being important. And the other thing we did not mention is total tumor volume, and it's prognostic across the board. You got a whole bunch of tumor, you're not going to do very well, and that's regardless of therapies. The clinicians need to weigh in about when to think about the therapies and the context of what other therapies are available. And that should be very individualized based on the genetics, the pace of the disease. There are patients who may have oligometastatic disease, it may need a little SBRT and not much more. There are a whole series of things we need to take into account. It's not just the scan.
Neeraj Agarwal: It's great to have option of Pluvicto in the clinic for our patients with MCR.
Daniel Petrylak: One other point, and again, this is seen in that particular study looking at the PSMA PET scans about the total tumor volume. Earlier treatment is better. Catch the patient early, make sure that you detect disease early. And I think that this is going to be the theme of the future.
Neeraj Agarwal: Yeah, I agree. I mean, even for ARPIs, earlier treatment is panning out to be better than later treatment.
Daniel Petrylak: Can I make one other point?
Oliver Sartor: Mm-hmm.
Daniel Petrylak: Very interesting thing Oliver mentioned about the cabazitaxel data and the AR mutations. So we're actually doing a trial right now with ARV-766, which is a PROTAC that targets the androgen receptor, particularly the androgen receptor mutations. And that's been found to be one of the biggest upregulators of PSMA. So we're going to do lead-in study looking at ARV-766 for approximately two weeks, pre- and post- PSMA PET scans, and then hit them with Lutetium-177. Really excited about this study.
Neeraj Agarwal: That's wonderful. Well, thank you very much for taking the time to share your experience of selection of patients for Pluvicto and other radioligand therapy.
Daniel Petrylak: Thank you.
Oliver Sartor: Thank you, Neeraj.