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Alicia Morgans: Hi, I'm so excited to be here with Associate Professor Jeremie Calais from UCLA. Thank you so much for being here with me today.

Jeremie Calais: Sure, my good pleasure, as always.

Alicia Morgans: Wonderful. I wanted to talk with you about a retrospective analysis of the use of PSMA PET in salvage radiotherapy that was discussed as a poster at ASCO 2023. Can you tell me a little bit about what was presented.

Jeremie Calais: Again, thank you very much for inviting me and giving me the opportunity to present the work. This work was done in collaboration with my radiation oncologist colleagues, so Dr. Clayton Smith and Amar Kishan who are really key in the use of PSMA PET at UCLA since the beginning. This study, because at UCLA we started to use PSMA PET quite early in comparison to the other sites in United States, we started in 2016, and very rapidly are referring oncologists, urologists, radiation oncologists, medical oncologists, they started to use the PSMA PET findings and act on it, especially the radiation oncologist because you see the disease so they can directly target it.

It's not just one change of a systemic therapy agent. They really target it, they may change the dose, they may change the radiation fields, they add concomitant systemic therapy or not. So they have multiple parameters they can play with. You see the images on the scan, so you cannot ignore what you see even though there are a lot of questions on how to treat these new findings on the PSMA PET scan. There is no actual good cooking recipe yet. We don't know exactly what to do with these new findings, but you cannot ignore them. So we were in this kind of paradigm.

In this situation you have a new diagnostic tool, we have rules that are established that are kind of reliable but done with other tools. Now we see new things, which is good, but we don't know how to use these new things. But people actually did it. And so we have now maybe 4 to 5 years of follow up. It's a retrospective study that looked at patients that were treated with salvage radiation therapy for biochemical recurrence after radical prostatectomy and following the PSMA PET scan findings. We were able to identify 200 patients like that. The median follow-up time was about 3 to 4 years and the PSA was 0.6 as a median. So, you can see not so low, but these were the patients that were actually treated with radiation therapy. We don't describe here all the ones that were not treated with radiation therapy, they had other types of management.

The first main finding is that, as always, as a general rule that in medical oncology, the more you have disease in solid tumors, the worse it is. It is confirmed with PSMA PET, even if you see the disease earlier, the more you have it, the worse it is in terms of outcome. And if you compare patients with M1 disease versus M0, whatever types of radiation therapy-based management they got, it is worse to have metastatic disease than nonmetastatic disease. There was almost 1.5 years of difference of progression-free survival after that. Then, the number of lesions matter. The more you have lesions, the worse it is, even if you treat them because most of the lesions were treated. This was kind of all-comers type of radiation therapy management. It was really a early-stage setting patient population. Patients had one to three lesions, so really oligometastatic disease. And even in that setting, the more lesions you have, the worse it was.

And then there was some more interesting findings. For example, we look at the effect of deescalation. Many people think that because the PSMA PET is the best imaging technique you can get, the most accurate, you can just treat what you see and you don't treat the rest. So deescalation for patients is a very convenient thought, and even for doctors. Some people did actually that. In fact, when you look at settings, let's take the example of patient that have metastatic disease, few lesions, no visible disease in the prostate bed, then there were some patients who were treated with metastatic disease therapy only and others that were treated with the metastatic-directed therapy, and in addition, systematic irradiation of the prostate for them. If you can compare the outcome of the two, patients who did not get their prostate bed irradiated recurred much more, and the others that got the prostate bed irradiated had a much lower recurrence rate, even though we were not seeing the disease on the PET scan.

So it really showed that we don't see the microscopic disease. That PSMA PET, I like to say it in these words, underestimate less the burden of disease than the other imaging modalities. So it's really the best one, but it's still not perfect. There is still a lot of things that you don't see.

Similarly, for patients who had no visible metastatic disease, no visible pelvic lymph node disease, just disease either in the prostate bed or nothing, some were treated just to the prostate bed, salvage radiation therapy just on the prostate for them, and some had that plus the irradiation of the pelvic lymph node. Again, the recurrence rates were lower in the patients who got the pelvic lymph node irradiated, but they were negative by the PSMA PET scan. So it really means that deescalation based on PET is, in that series of patients, of course we don't have control group, nothing was standardized, it seems that you undertreat patients by doing that.

After that, looking at these results, if you have a negative PSMA PET scan, you should still treat the patient how you were considering to treat the patient before doing the PET scan. And you can use the PET scan just to add additional sites, so more on the upstaging side, but not really on the down-management.

Alicia Morgans: I think that's so interesting and what an important finding, to your point. The way I describe it to patients is that a PET scan is not a microscope. We can't see down to the level of the cell. We can only see, I don't know if it's hundreds of thousands or even millions of cells when they're in a group. So this makes sense, but we haven't had data to really show it. I also love the explanation of, it is not uncommon for even physicians to say, "Can you just do SBRT to those pelvic lymph nodes and then avoid the entire field and the prostate itself?" But clearly that's not the way to go, at least according to this data. It's just very provocative, really important.

Jeremie Calais: Well, I do have all kinds of stories. I do have the story of a patient with a single, for example, perirectal node or a single spine node treated with SBRT just there, nothing else elsewhere. No prostate bed irradiation, no whole pelvic lymph node irradiation, no systemic therapy agents, no hormonal treatments. And then 2, 4 years after, still PSA zero. So it does exist. But when you take groups of patients, then you realize it's not the rule.

Alicia Morgans: But how many patients were in this study.

Jeremie Calais: Here we're talking about 200 patients, and then if you subdivide them with the same characteristics, same treatment management, you end up with very, very small groups. Like, you compare the outcome of 30 to 30 other patients.

Alicia Morgans: And so if we can find that difference in such small subgroups, I think it is a compelling message. Even if those one-off patients exist here or there, it's a very, very interesting and important message. Were there patients in this particular analysis treated with systemic therapy intensification or was this really just radiation?

Jeremie Calais: No, they had radiation plus/minus ADT. At the end, half or almost two-thirds of the patient got some form of ADT. Usually it's short-term in this BCR population. Some had long-term, I think 18 months, but it was maybe 10% of them. So there was 6 months of ADT. But then if you start to put the exact same management, prostate bed plus ADT, prostate bed alone, prostate bed plus ADT and pelvic lymph node, prostate bed and pelvic lymph node, then you end up with very small cohorts.

Alicia Morgans: Very small, yeah.

Jeremie Calais: And so that's why it's not easy to compare. So I think now people understood that, people understood the value of integrating PSMA PET into the clinical trials. There are many currently ongoing clinical trials that have integrated PSMA PET into their randomization algorithm, and so I hope that's maybe, it'll take time because it's early setting, but in the next year, maybe 5 years, we'll have more answer on how to use. Okay, when you have that finding on PSMA PET scan in a patient at that disease stage, this is the best treatment you should do and that. We'll have to prove that for each. I think we're going there, it'll just take some time.

Alicia Morgans: Absolutely. Yeah. Overall, a 200 patient cohort is actually really a big group, it's just that we treat this disease state so heterogeneously that it breaks them into these tiny groups for these comparisons. But really interesting that you can still see a signal for some of those breakdowns and comparisons, even with those small groups. Where does your group go next? What are you investigating next within the data that you have?

Jeremie Calais: This was just for the BCR setting, but you can do that for multiple disease stages. We have that before radical prostatectomy. We have great studies that will come up there. Our group presented some data also at ASCO this year about the value of PS PET before surgery and with the pelvic influence staging in comparison to pathology. Then you can move stage later. So in the CRPC setting, we have a study in the very high-risk BCR population with a short doubling time. So all the EMBARK-like populations for all the AR-targeted agent studies approvals.

And here, again, it's how you use the new information that was not integrated into the rules before, how you use it, how it impacts outcome. And so we really have to follow these patients. So it's a lot about follow up, how to follow these patients, identify some PSMA PET patterns, and see how, at each disease stage, what they mean and how to treat them at best. So that's what we're doing a lot.

We studied, again, in 2016, we're merging data with other sites. So now at 5, 6, 7 years since the first patient, so we can start harvesting some outcome data, it'll take time. And then we have the whole PSMA-targeted therapy era and field of interest, and so how to use PSMA imaging, integrate that with PSMA-targeted therapy, how to refine the PSMA-targeted therapy way of administering treatments. So a lot of refinement to how to use these PSMA techniques. And then there are new targets, new radionuclides that will come as well.

Alicia Morgans: Well, it's wonderful that we continue to make advances here and certainly I'm hearing about new imaging modalities and ligands and these radiopharmaceuticals that are coming out for improved imaging and different imaging. I think it's so interesting that we feel like we've finally made such progress with PSMA, just in terms of the gallium and the Pylarify agents that we have now, but there are more on the way. So I love that you and the nuclear medicine docs always keep us moving forward. What would you say, based on the data that you presented to patients in clinic, what would your messages be to those patients with biochemical recurrence and maybe some findings of lesions, whether they're pelvic recurrences or even metastatic on PSMA PET?

Jeremie Calais: First of all, I would say to patients, "Do a PSMA PET scan, you have nothing to lose. It's just one scan. There is no side effects, there is no real downside. And now about the information you get, don't be disappointed if you have a negative scan." So in that setting, a patient will say, "Okay, I have PSA of 0.1. Should I do the scan now or should I wait to get more chance to get a positive scan or should I wait 0.5? But then maybe it's too late to initiate a therapy for that." So there is, I think, no good answer. That's a ratio.

Again, I think if you see it's not to deescalate the treatment management, I think you can try to do the scan at whatever PSA. Of course your expectations should be very low in terms of getting a positive scan when the PSA is 0.1. If you understand that, you say, "okay, maybe there is a tiny chance to see something, I just want to make sure I'm not in the tiny chance." Sometimes it happens. Sometimes I have patient with PSA .15 and you see a spot in the lymph node or in the skeleton and then it impacts. Very rare, but most of the time you don't.

So then you just do, with a negative scan, the treatment as you would have done without the scan and usually it reinforces the outcome of treatment because you select patients that have nothing else elsewhere, at least you have no sign of something else elsewhere. It's good to have negative scan. Louise Emmett presented a 3-year outcome follow up study in the same setting. They showed that when the patients have a negative scan, they do better when they are treated with salvage radiation therapy to the prostate bed than without. So a negative scan is good and it's a better sign and it's a sign to treat. So I think it's important for patient to understand this deescalation thing.

And then when you can see disease elsewhere, then I don't know if we know the best. Is it good to radiate the lesion, to use systemic therapy agent? That I don't know. Usually I stop here and say, "Go see your radiation oncologist, your medical oncologist, and you see with them."

Alicia Morgans: Yes, yes. But to your point, you should probably still radiate the prostate and pelvic bed and then consider adding on maybe the radiation, the SBRT, to those other lesions that you may see outside of the pelvis. But it's really interesting. I think there are clinical trials that are trying to investigate just this and to understand if we do do SBRT to all visualizable lesions, even, as it may be, after salvage radiation to the pelvis and then we see an additional biochemical recurrence, now what do we do and how do we best use systemic therapies, targeted radiation, or advances to try to treat these patients? No one quite knows what to do.

Jeremie Calais: Yeah. There is one thing, is that the disease you see on PET imaging, which is usually much earlier than what you see on conventional imaging, I think is of less severity, less gravity than the disease you see on conventional imaging. So that's also to put in the weight in the balance.

Alicia Morgans: Absolutely. Well, thank you so much for walking me through this and certainly thank you for presenting this data and it was a wonderful conversation at GU ASCO and in the poster discussion and your work certainly added to that, so thank you for your time and your expertise today.

Jeremie Calais: Thank you very much. Always a pleasure.