Linda Budzinski: Can you comment on your experience with PYLARIFY DCF PyL and how it impacts your management of men at staging? Does it potentially change your surgical approach? Second, do you think these PSMA scans will replace conventional imaging and staging? And third, in the BCR setting, what is your threshold for PSMA scanning if would you have one?

Micheal Gorin: With respect to the first two questions, which surround staging, I do think it's helpful in patients who appear on the basis of conventional imaging to be clinically localized, but for whom you're worried that they have metastatic disease. We found in a phase 2 study that we did leading up to the OSPREY study, where we took patients with high-risk disease and we imaged them, that there was 25 patients in the study, but 1 of the 25 actually had widespread metastatic disease. And this was clearly a patient for whom, if we did a radical prostatectomy, we probably subjected them to unnecessary harms of treatment. So it's not a large percentage of patients, but I do think that there is a significant number of patients for whom you would just avoid definitive treatment altogether.

And then we have the other class of patients, who ARE probably about 20% or so, where we do find a lymph node metastasis. Now, if the lymph node metastases are the lymph node template, I do think it's very reasonable to continue to proceed with surgery in them. But at least now when you perform the surgery, you really have some anatomic information with which to proceed, to really make sure that you clean out that lymph node basin sufficiently to eradicate the nodal disease. You could take the other standpoint, though, and say, well surgery, the literature supporting performing a radical prostatectomy pelvic lymphoma dissection, and in one disease, is not really founded in clinical trials so much. But we do know that radiation therapy with androgen deprivation does seem to be a very good treatment approach for these patients on the basis of things like the STAMPEDE trial and whatnot.

And so perhaps this is a patient who you would convert from a surgical approach to one where you give them radiation therapy with androgen deprivation, which should have at least a lower side effect profile in terms of urinary symptoms. So I think that's really how I'm using it, is looking for, one, frank metastatic disease, and then two, large volume or out-of-field nodal disease for whom I would avoid surgery in, and go instead either with systemic therapy or radiation with androgen deprivation. Interoperatively, I don't think it really does much to change my approach, other than to just be far more meticulous with the pelvic lymph node dissection and make sure that the base and where the positive signal is found has been cleaned out. I think it's really more though about what happens prior to you getting to the operating room.

That third question about when's the ideal PSA level to order this, well, I think, really, when I'm using PSMA imaging for, in patients with biochemically recurrent disease, as a urologist, really being interested and really focusing on patients who have had radical prostatectomy and now biochemical recurrence, is to determine who is an appropriate candidate for salvage radiation therapy and who is not. We know that the lower the PSA level is at the time point at which salvage radiation therapy is delivered the better the outcomes. So, really, anyone who crosses that AUA threshold criteria for biochemical recurrence or someone who has a persistently elevated PSA level after radical prostatectomy, is someone for whom I'm going to order the scan in, sooner rather than later.

Now, granted, as you recall, probably recall from the CONDOR trial data that I showed, it's probably about 30 to 40% of patients at a PSA less than 0.5 that we see something. But when you do see something, if it's outside of the salvage radiation field, that's someone for whom I could have avoided a potentially futile treatment. So that's how I use it in that context.

Steven Rowe: There are a number of nomograms out there now that sort of suggest which patients are more likely to see something on the scan in the biochemical recurrence setting, but none of those nomograms are there any groups of patients in whom you never see anything on the scan. And I think what Dr. Gorin said is true and leads to the conclusion that even the negative scan has important potential decision-making behind it, in that if it's negative, you don't see anything outside of what your salvage radiation field would be, it's very likely that the disease is small-volume, relatively indolent in the salvage radiation field. And so even a negative scan, I think, makes decision-making more confident.

Micheal Gorin:  While everything we just said we believe to be logical, we don't have clinical trials to show that this in fact does improve patient outcomes. So we're operating with the best of intents right now, but not the best of knowledge.

Linda Budzinski: How do you interact with urologists or how would you like urologists to interact with their medicine physician colleagues to facilitate the reads for these scans?

Steven Rowe:  Great question. I guess the way I interact mostly is I just started to every tour board and multidisciplinary conference I could find, many of which I was directed to by Dr. Gorin. And that was super helpful. So people basically got used to seeing my face around, they got used to asking me questions and valuing that I would maybe go out on a limb and provided an opinion when they were faced with a scan with some uncertainty. But I do think it is a tremendously important that that if, say, a radiologist or a nuclear medicine physician is using a particular read paradigm, CPS, MI-RADS, or PROMIS, that they discuss that with their urologist and that they make sure that everyone's on the same page so that we're using the same terms, we know what those terms mean, and that the read paradigm, or just a freehand dictation, whatever it may be, is providing the information that the urologist needs to know.

One example might be that if I have some uncertainty about a lymph node that's outside of what I know the pelvic lymph node dissection template that Dr. Gorin can get to intraoperatively is, that I may have to take that more seriously and emphasize that more in the read. And hopefully that's helpful to the urologist, to at least know that and their conversations with the patient, how they counsel the patient, that there is a finding that may impact their suitability for surgery or their outcomes from the surgery.