Steve Y. Cho: Yes.
Phuoc Tran: So we're going to be talking today about biochemical recurrence in the PSMA PET era. Dr. Cho and I have an interesting history in that he has extensive experience, particularly in the early days of PSMA PET when we both shared some time at Hopkins. So please tell me about how you think about biochemical recurrence now in the PSMA PET era.
Steve Y. Cho: It's a pleasure to be here and to be a colleague at the same institution again. So PSMA PET is basically a modality that we have been wishing for in the bone scan CT era with increased sensitivity for detection. Now with increased sensitivity comes both advantages and disadvantages. I think the advantage, obviously, I mean, vastly many of these patients are detected in the negative conventional imaging setting. And so you actually have potentially actionable metastases and with lower PSA levels. And so you're giving actionable targets from imaging, especially for metastasis directed therapy.
And so it's very, very helpful in that setting.
However, with that comes from an imaging perspective, what do you call imaging positive? It's not always dichotomous for us. And so I think one of the challenges has been to call PSMA positivity and to make sure that we're reading things correctly and in the appropriate clinical setting so that we can provide the appropriate information for either our radiation oncologist or oncologists in terms of treatment.
Phuoc Tran: Well, some of this is becoming more common knowledge, but it wasn't too long ago that many folks didn't know when to order a PSMA PET at what PSA levels it was likely to be useful and there would be detectable lesions. Do you mind going over that a little bit for our audience?
Steve Y. Cho: Currently, I think with the clinical trials that have done in the biochemical recurrent setting, really we're looking at PSA levels of 0.2 to 0.5. And in that setting, these patients had basically detection rates that were fairly high detection rates. Now, if you get to lower PSA levels, then you get to more difficult situation where you don't have a lot of study data, but clinically you're getting ultra low PSA levels.
And so many times in those settings, you may have negative PSMA PET-CT studies, which may frustrate the referring clinician or the patient. Or people may feel compelled to read these maybe more sensitively than they need to, and then you get false positives reports. I think in the appropriate setting of 0.2 to higher, sometimes you can also, and there's been a learning curve in the community to find out what the pitfalls are, not call things that are false positives.
Ganglia are one area that are very easily, I think, most people understand that area. Another area has been things that may cause false positivity. Ribs, low uptake in the ribs is a common area. So I think there is a learning curve and there is growing expertise in how we read these.
But I think, again, I think not everything that's positive is positive. And being very judicious about reading this and having discussions and having follow up confirmatory studies or having follow up PSMA PET-CT studies in the appropriate setting, I think is important not to potentially over-treat these patients with false positives.
Phuoc Tran: Speaking upon that a little bit more, the specificity of the PSMA PET-CT scans, can you tell us and the audience a little bit about, I realize you just went over all these potential false positives, but give us some insights into really the specificity of the tests and how confident folks can be. For instance, if there is conventional imaging negative tests, but PSMA positive.
Steve Y. Cho: Yeah. So in the studies that have been completed with Gallium and Pylarify with the DCFPyL, F18 PSMA PET, in the biochemical recurrence setting, we typically read these fairly sensitively as they tend to have fairly specific uptake, especially in small lymph nodes. Because small lymph nodes that are typically negative by conventional CT criteria, if we have positivity, usually those areas, we have fair confidence that they're positive.
In the primary initial staging setting, it tends to be fairly specific, but not as sensitive. So a lot of times there may be absence of PSMA PET lymph node detection or metastatic disease detection, does not mean that there's not disease there. And so I think you have to be careful about which setting that you're reading and how sensitive you're reading these.
But in those two settings, that's how we typically approach them. But I think we're always looking very closely at those small lymph nodes that may have some level of positivity and then trying to figure out confirmatory imaging and testing to see or follow up imaging to see if there truly are true positive or not and if they're actionable.
Bone is a different area where we have to be very... I think there can be a fair amount of non-specificity and low uptake. And so a lot of times you want to have a relatively high level of uptake in bone lesions and looking for correlative bone findings. But you do have precursor lesions that are very early bone metastatic disease that can be PSMA positive, but CT bone negative.
Those are the areas that oftentimes that does give us some pause. But I think if it's relatively focally hot or would be in the PSMA-RAD criteria, PSMA-RAD4, I think those are usually fairly suspicious for metastatic disease, especially if you have more than one lesion and maybe actionable by itself. But if you have low uptake in bone, and without much CT bone abnormality, then I would say to be more cautious and to be judicious about calling those positive.
Phuoc Tran: Okay, great. So PSMA PET-CT has been a disruptive technology, but I think what you're really saying is clinical context is still important. Utilizing pretest probability in the following the PSMA PET is also still important, even for a disruptive technology like we have. The final question, and it's a question that's been asked a lot at this meeting, is please put into context how you believe the patients that were enrolled on EMBARK would fare after PSMA PET imaging. What do you think their distribution of patients with strictly biochemical recurrence or non-metastatic disease versus obviously maybe a fair number of those patients actually showing PSMA positive disease?
Steve Y. Cho: Yeah. Just looking at that study a little bit in preparation for a talk, I think it's the percentage is relatively high percentage of these patients who are conventional imaging negative were positive on PSMA PET. So I think that's our clinical experience. And I think it's the question in our field is clinically, many of the times you can't ignore these. Assuming that they're imaging that it truly is a positive lesion and is verifiably positive, do you act on that or not?
I think clinically you feel compelled to act, but in a clinical trial setting using conventional imaging endpoints, you may be jumping the gun. And so you may be putting your clinical trial at risk. I think that's the dilemma that we're all facing in the field that at the early days of PSMA PET development, we knew this was coming where the new test is more sensitive.
And is this just stage migration without much change in outcome?
I do think there needs to be probably necessary judicious, necessary clinical trials that are appropriate designed with all of the imaging, with PSMA conventional imaging as Prostate Cancer Working Group 4 recommended as maybe a bridging study. But I do think we do have to move on because I think everyone is voting with their feet of not doing bone scans, which are getting more and more rare. And clinical trials are getting harder and harder to enroll if you require bone scans upfront.
Phuoc Tran: Yeah. No, I think that's well said. This is, like I was saying before, disruptive technology. As much as we would like to stall progress, like you said, patients for sure are coming and voting with their feet, so to speak, on the way that we should proceed. So with that, I'd like to thank you for your time and your expertise. And thank you.
Steve Y. Cho: Great. Thank you. It's been a pleasure.