PSMA RLT for Oligometastatic Disease "Presentation" - Amar Kishan
April 14, 2025
At the 2025 UCSF-UCLA PSMA Conference, Amar Kishan examines PSMA radioligand therapy for oligometastatic prostate cancer. He reviews phase II trials showing progression-free survival benefits with metastasis-directed therapy, but notes limited durability. Dr. Kishan highlights treatment intensification challenges, contrasting SATURN's modest results when adding hormone therapy with RAVENS' negative findings for radium-223. He proposes PSMA-RLT as a promising alternative that could spare ADT toxicity while targeting micrometastatic disease, citing encouraging BULLSEYE trial results.
Biography:
Amar U. Kishan, MD, Professor, Vice Chair of Clinical and Translational Research, Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA
Biography:
Amar U. Kishan, MD, Professor, Vice Chair of Clinical and Translational Research, Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA
Read the Full Video Transcript
Amar Kishan: All right, thank you very much. I'll be talking about PSMA RLT for oligometastatic disease, a case for its use. Here are my disclosures. So we'll be talking very briefly about rationale and evidence for MDT, the need for systemic therapy intensification, and then an overview of the literature here, or at least the ongoing studies.
So we're all familiar with this. Oligometastatic disease is a disease state characterized by the presence of a limited number of clinically detectable metastases, 1 to 5 generally. And it can be synchronous in the de novo, newly diagnosed setting, or it can be metachronous in the recurrent setting. And it could encompass a couple of different possibilities: it’s really, truly indolent biology that is not going to spread further; it could be aggressive biology that we just capture early; or it could be what we traditionally would call subclinical disease that we can just see because of better imaging.
The goal of MDT across cancers would be the idea that many patients with recurrent disease are relapsing in a few locations—three or fewer in most series. Ablating all sites of disease in these patients might delay the initiation of systemic therapy. We just heard nobody wants to go on systemic therapy and all the side effects of that, and if on systemic therapy, it might allow you to prolong the effect of therapy. If patients truly have limited volume of disease, then potentially this could be curative as well, the same way that salvage radiation can be curative after prostatectomy.
Obviously, we don't have time to go over the details, but there have been multiple phase II randomized trials evaluating various permutations of MDT, specifically in oligometastatic prostate cancer. We have the STOMP and ORIOLE trials that compared MDT versus observation, showing benefit in progression-free survival. We have the EXTEND trial that showed that there was a benefit of adding MDT to intermittent ADT, and that was, again, progression-free survival as well as gonadal progression-free survival. We have the RADIOSA trial, which I'll talk about in a second, that looked at if it helps to add six months of ADT to MDT—did improve progression-free survival, but not eugonadal progression-free survival. And then in the mCRPC setting, which I won't be talking further about, we have the ARTO trial that shows a benefit to MDT in progression-free survival.
Very recently at ASCO GU, there was the WOLVERINE meta-analysis that was presented, which looked at all of these trials and presented a very close, statistically significant overall survival benefit to MDT. However, is this durable? If we look at the long-term results of STOMP and ORIOLE, which you can see here, obviously the MDT curve is superior to the observation curve, but in both groups, by three to five years post-therapy, very few patients are rendered free of disease. So it's not particularly durable.
What if you look at more intense treatment? So in the EXTEND trial, for instance, this is eugonadal progression-free survival on the left there. The combined group got intermittent ADT plus MDT. And actually, if you follow those curves out, it looks pretty good until you look at the bottom, where there's one patient that's contributing that data point. So there's not that much data here. And even then, it's maybe, what, 60% of patients of one person at risk that really was free of disease.
The RADIOSA trial, which I mentioned, was asking the question, if you add six months of ADT to MDT, does that meaningfully alter the natural history of disease? Progression-free survival, of course, was improved by that because the ADT itself will suppress PSA production. But if you look at what I'm showing here, which is eugonadal progression-free survival, the curves for MDT plus ADT and just MDT are actually completely overlapping, suggesting that it is not durably changing the natural history to add the six months of ADT.
We have data on the patterns of progression. This was published many years ago and is still valid today. You have this group of patients that has durable control after MDT, maybe 28% of patients in this retrospective series. The vast majority of patients progress—some, maybe 45%, have oligoprogression, so you can do MDT again, but it'll have limited returns over time. And 28% of patients have poly-progression, which obviously is something we want to try to avoid.
So how can we intensify therapy? One approach would be to use highly potent, hopefully cytocidal doses of ADT or ADT mechanisms like androgen annihilation, which we studied here at UCLA on our SATURN trial. Here, patients got six months of apalutamide, leuprolide, and abiraterone in addition to MDT to PSMA-defined disease. Bottom line, we found that the percentage of patients who maintained an undetectable PSA six months after testosterone recovery—so it's a true evaluation of disease that we would want to be undetectable—was only 50%. On the one hand, that's pretty good. If we had not done this, that number would likely be a lot lower, again, with testosterone recovery. But grade 3 toxicity was seen in 20% of patients related to the medications they were provided. And ultimately, 50% is not a good number. That's not what we should aspire to.
Another way of intensifying therapy would be with a radioligand. So this has been studied in the RAVENS trial. The results were presented last year at our national meeting and will be published very soon. This trial randomized 64 men with recurrent prostate cancer and at least one bone lesion, three or fewer on conventional imaging, or five or fewer on advanced imaging, to SBRT alone or SBRT plus six cycles of radium-223. The median PSA was 5.6. Most of these patients truly had bone-only disease. Ninety-seven percent had three or fewer lesions. Their primary endpoint was a composite endpoint of progression-free survival.
A thank you to Dr. Kiess, I believe is in the audience, for providing these figures. But essentially, the trial was negative. There was no benefit; progression-free survival was 10.5 months versus 11.8 months, numerically worse, actually, with the intervention. Now, interestingly enough, they did verify that there are some patients, regardless of arm, who have a mutational signature in TP53, RB, BRCA1/2, or ATM, that are more likely to have a rapid poly-progression. Maybe that's the specific group of patients that we could investigate further when looking at other clinical trials. But unfortunately, intensification with radium didn't work.
So systemic intensification is warranted. ADT, androgen annihilation, maybe you can do OK with this, but there's a lot of toxicity, and they have all the side effects of ADT, and it's only 50% of patients at six months of testosterone recovery. That's not great. Intensification with radium didn't work. Maybe this is limitations of the agent—it’s bone-only, and you need an osteoblastic reaction. Or maybe the burden of disease isn't enough.
PSMA-based RLT makes sense here as a way of sparing ADT and targeting all micrometastatic niches. We have some early data from the BULLSEYE trial, which was presented a couple of years ago. This was men with metastatic hormone-sensitive prostate cancer, fewer than five lesions, and a PSA doubling time of less than six months, randomized to two to four cycles of lutetium-617 versus deferred ADT. The primary endpoint was progression, and they actually showed an improvement in progression—10% with radioligand therapy versus 77% without it.
We have our LUNAR trial, which completed accrual here. Results are expected soon, where we randomized men to two cycles of neoadjuvant lutetium PNT2002 followed by SBRT versus SBRT alone. So that will hopefully provide us some answers. And then we have the registrational PSMA-DC trial. Dr. Kiess is the PI of that trial. It's a 1-to-1 randomized trial in oligorecurrent disease, randomizing to SBRT versus SBRT and four adjuvant cycles of lutetium-617. You can see that these patients must have negative conventional imaging and five lesions on PSMA PET or fewer, and the primary endpoint there is metastasis-free survival on conventional imaging.
And just another table of all potential studies in this regard. Thank you very much.
Amar Kishan: All right, thank you very much. I'll be talking about PSMA RLT for oligometastatic disease, a case for its use. Here are my disclosures. So we'll be talking very briefly about rationale and evidence for MDT, the need for systemic therapy intensification, and then an overview of the literature here, or at least the ongoing studies.
So we're all familiar with this. Oligometastatic disease is a disease state characterized by the presence of a limited number of clinically detectable metastases, 1 to 5 generally. And it can be synchronous in the de novo, newly diagnosed setting, or it can be metachronous in the recurrent setting. And it could encompass a couple of different possibilities: it’s really, truly indolent biology that is not going to spread further; it could be aggressive biology that we just capture early; or it could be what we traditionally would call subclinical disease that we can just see because of better imaging.
The goal of MDT across cancers would be the idea that many patients with recurrent disease are relapsing in a few locations—three or fewer in most series. Ablating all sites of disease in these patients might delay the initiation of systemic therapy. We just heard nobody wants to go on systemic therapy and all the side effects of that, and if on systemic therapy, it might allow you to prolong the effect of therapy. If patients truly have limited volume of disease, then potentially this could be curative as well, the same way that salvage radiation can be curative after prostatectomy.
Obviously, we don't have time to go over the details, but there have been multiple phase II randomized trials evaluating various permutations of MDT, specifically in oligometastatic prostate cancer. We have the STOMP and ORIOLE trials that compared MDT versus observation, showing benefit in progression-free survival. We have the EXTEND trial that showed that there was a benefit of adding MDT to intermittent ADT, and that was, again, progression-free survival as well as gonadal progression-free survival. We have the RADIOSA trial, which I'll talk about in a second, that looked at if it helps to add six months of ADT to MDT—did improve progression-free survival, but not eugonadal progression-free survival. And then in the mCRPC setting, which I won't be talking further about, we have the ARTO trial that shows a benefit to MDT in progression-free survival.
Very recently at ASCO GU, there was the WOLVERINE meta-analysis that was presented, which looked at all of these trials and presented a very close, statistically significant overall survival benefit to MDT. However, is this durable? If we look at the long-term results of STOMP and ORIOLE, which you can see here, obviously the MDT curve is superior to the observation curve, but in both groups, by three to five years post-therapy, very few patients are rendered free of disease. So it's not particularly durable.
What if you look at more intense treatment? So in the EXTEND trial, for instance, this is eugonadal progression-free survival on the left there. The combined group got intermittent ADT plus MDT. And actually, if you follow those curves out, it looks pretty good until you look at the bottom, where there's one patient that's contributing that data point. So there's not that much data here. And even then, it's maybe, what, 60% of patients of one person at risk that really was free of disease.
The RADIOSA trial, which I mentioned, was asking the question, if you add six months of ADT to MDT, does that meaningfully alter the natural history of disease? Progression-free survival, of course, was improved by that because the ADT itself will suppress PSA production. But if you look at what I'm showing here, which is eugonadal progression-free survival, the curves for MDT plus ADT and just MDT are actually completely overlapping, suggesting that it is not durably changing the natural history to add the six months of ADT.
We have data on the patterns of progression. This was published many years ago and is still valid today. You have this group of patients that has durable control after MDT, maybe 28% of patients in this retrospective series. The vast majority of patients progress—some, maybe 45%, have oligoprogression, so you can do MDT again, but it'll have limited returns over time. And 28% of patients have poly-progression, which obviously is something we want to try to avoid.
So how can we intensify therapy? One approach would be to use highly potent, hopefully cytocidal doses of ADT or ADT mechanisms like androgen annihilation, which we studied here at UCLA on our SATURN trial. Here, patients got six months of apalutamide, leuprolide, and abiraterone in addition to MDT to PSMA-defined disease. Bottom line, we found that the percentage of patients who maintained an undetectable PSA six months after testosterone recovery—so it's a true evaluation of disease that we would want to be undetectable—was only 50%. On the one hand, that's pretty good. If we had not done this, that number would likely be a lot lower, again, with testosterone recovery. But grade 3 toxicity was seen in 20% of patients related to the medications they were provided. And ultimately, 50% is not a good number. That's not what we should aspire to.
Another way of intensifying therapy would be with a radioligand. So this has been studied in the RAVENS trial. The results were presented last year at our national meeting and will be published very soon. This trial randomized 64 men with recurrent prostate cancer and at least one bone lesion, three or fewer on conventional imaging, or five or fewer on advanced imaging, to SBRT alone or SBRT plus six cycles of radium-223. The median PSA was 5.6. Most of these patients truly had bone-only disease. Ninety-seven percent had three or fewer lesions. Their primary endpoint was a composite endpoint of progression-free survival.
A thank you to Dr. Kiess, I believe is in the audience, for providing these figures. But essentially, the trial was negative. There was no benefit; progression-free survival was 10.5 months versus 11.8 months, numerically worse, actually, with the intervention. Now, interestingly enough, they did verify that there are some patients, regardless of arm, who have a mutational signature in TP53, RB, BRCA1/2, or ATM, that are more likely to have a rapid poly-progression. Maybe that's the specific group of patients that we could investigate further when looking at other clinical trials. But unfortunately, intensification with radium didn't work.
So systemic intensification is warranted. ADT, androgen annihilation, maybe you can do OK with this, but there's a lot of toxicity, and they have all the side effects of ADT, and it's only 50% of patients at six months of testosterone recovery. That's not great. Intensification with radium didn't work. Maybe this is limitations of the agent—it’s bone-only, and you need an osteoblastic reaction. Or maybe the burden of disease isn't enough.
PSMA-based RLT makes sense here as a way of sparing ADT and targeting all micrometastatic niches. We have some early data from the BULLSEYE trial, which was presented a couple of years ago. This was men with metastatic hormone-sensitive prostate cancer, fewer than five lesions, and a PSA doubling time of less than six months, randomized to two to four cycles of lutetium-617 versus deferred ADT. The primary endpoint was progression, and they actually showed an improvement in progression—10% with radioligand therapy versus 77% without it.
We have our LUNAR trial, which completed accrual here. Results are expected soon, where we randomized men to two cycles of neoadjuvant lutetium PNT2002 followed by SBRT versus SBRT alone. So that will hopefully provide us some answers. And then we have the registrational PSMA-DC trial. Dr. Kiess is the PI of that trial. It's a 1-to-1 randomized trial in oligorecurrent disease, randomizing to SBRT versus SBRT and four adjuvant cycles of lutetium-617. You can see that these patients must have negative conventional imaging and five lesions on PSMA PET or fewer, and the primary endpoint there is metastasis-free survival on conventional imaging.
And just another table of all potential studies in this regard. Thank you very much.