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Geoffrey Sonn: Welcome to the second case of our Clinical Case-Based Learning Virtual Tumor Board for Advanced Prostate Cancer. I'd like to introduce study two or patient two, Mr. Michael Miller, demonstrating a case of prostate cancer recurrence.

This is a 69-year-old man with a history of coronary artery disease managed by two stents placed in 2017, Paget's disease and localized prostate cancer, Gleason score 3+4, pathologic T2N0M0 on radical prostatectomy, which he underwent in February 2015. His PSA never dropped to an undetectable level, and he was subsequently treated with salvage radiation and ADT for two years, from October of '15 through March of '18. His PSA nadired at an undetectable level during ADT but then became detectable after stopping ADT two years later at 0.05 and then began to rise over the course of the next year. In July of '21, his PSA rose to 0.59, and he underwent conventional imaging with a CT and a bone scan.

Two months later, he went on to have a PyL PSMA PET. Before we review his imaging, I want to provide a bit of additional information about Mr. Miller. He is still working and owns his own business and travels regularly. He is reticent to go back on ADT because of concerns about it slowing him down as well as his heart health. He takes aspirin, a statin, and metoprolol for his coronary artery disease and he is otherwise in excellent shape. He's married, has two kids, one in grad school and one working. So I would now like to turn this case over to Andrei for review of his imaging.

Andrei Iagaru: Thank you, Jeff. So here we have the MDP bone scan. We have whole-body acquisitions in anterior and posterior projection, as well as a few spot views to focus on areas of interest here. This is an analog of calcium, so it goes to areas of increased bone formation, including sclerotic bone metastasis, hence its role in detecting these lesions in cancers that lead to osteoblastic metastasis.

So we look for symmetry versus asymmetry, normal versus abnormal uptake, and pattern recognition. The uptake in the left shoulder is probably degenerative disease. There is abnormal uptake in the left iliac wing. It is heterogeneous and involves a large part of the study, and this goes in line with the history of Paget's disease, so that is not an episodic disease. This is excretion into the bladder. There is a small focus of uptake in the medial condyle of the distal right femur that is again, degenerative disease, unlikely to be a metastasis.

Now, if we go to the PyL scan ... Here we go ... Just with the other example, I look at the projection image. I look for normal versus abnormal. There are areas that stand out in the inguinal region, as well as in the pelvis. Again, we see some low-grade uptake in the axillary lymph nodes that are nonspecific, and we see some low-grade uptake in the left iliac region as well.

So if we review these images, starting from the pelvis and going cranially, we notice in the inguinal region, the presence of enlarged lymph nodes with focal intense uptake. Although not a typical pattern of spread, the appearance on both CT and PET makes them suspicious for metastatic prostate cancer. And I would like to draw your attention to the contralateral inguinal lymph nodes, which are normal in size and have very low-grade PyL uptake, those are likely inflammatory. As we move cranially, we see the presence of a left obturator lymph node with focal uptake as well as a right perirectal focal uptake in the perirectal fat that is highly concerning for metastatic disease. And as we go higher up, we see the presence of other lymph nodes, including in the left common iliac chain.

Now, if we put this on a bone window, we can appreciate the findings on CT that are compatible with Paget's disease as well as the low-grade uptake on PET. Again, PSMA is not prostate-specific, it is overexpressed in prostate cancer, but it can be seen with other etiologies, including Paget's, including fibrodysplasia, and including fractures. So the appearance on CT as well as the pattern of uptake is very helpful in interpreting these images.

So to summarize, Paget disease in the left iliac on CT, on bone scan, and on PyL PET, as well as the presence of inguinal obturator common iliac and perirectal lymph nodes. Those lymph nodes are concerning for recurrent prostate cancer. Back to you, Geoff.

Geoffrey Sonn: Thanks, Andrei. That's very helpful. So before we discuss our options, let's just go back through this case quickly one time. Again, to summarize, this is a 69-year-old man with coronary artery disease, Paget's disease, who underwent radical prostatectomy for Gleason 3+4 prostate cancer in 2015. His PSA never became undetectable so we went on to salvage radiation therapy and ADT for two years. His PSA stayed low on ADT, but two years later, it began to rise and is now at 0.59 with, as we see, nodal disease in multiple different spots all within the pelvis. So the question then for the group is what should be the next step for this patient? So maybe we can start with Hilary to hear what your thoughts are about whether radiation would be a good option for him and where you would radiate.

Hilary Bagshaw: So I think the first important thing to understand if anyone has had radiation, is when was it and what did they radiate? So it sounds like this was in 2015, so six years ago, which is favorable if we are going to go back and re-irradiate or overlap in an area, the longer out from radiation, the more comfortable we are with re-irradiation or radiating an adjacent area.

The next important thing to understand would be, what did the fields look like? So as radiation oncologists, we often get the images or the files, of the DICOM files of the plan so that we can really understand what they treated, to what dose, et cetera. I could maybe hope that this patient only had fossa radiation, which is a much smaller field than if he was treated to his pelvis. In 2015, that was probably more common across the country. And if that was the case, then I would probably recommend moving forward with radiation to the pelvic nodes and the inguinal nodes. So basically kind of patching on a field, avoiding his prior radiation in the prostate bed, trying to encompass all the sites of detectable disease on the PET scan, including the perirectal node, and then boosting the gross nodes, the avid nodes to a slightly higher dose than what we would give, kind of a prophylactic dose to the rest of the nodal basin.

I would also encourage them to meet with a medical oncologist to talk about hormone therapy. I know he's a little bit resistant to it, but I would talk about how it is beneficial, especially for gross disease, and that it enhances the efficacy of the radiation. Just given the volume, A, it could have some cytoreduction, so making the node smaller, and making it a little bit easier for us to boost them. And then B, we know there is a benefit with nodal disease. But I'd turn it back to Alicia on that.

Alicia Morgans: Well, thank you. I would agree with you. I know that he is hesitant, and he has good reason. He does have past experience, and he has coronary artery disease. But I think that I would agree 100%, that I would recommend if he is willing to at least try, maybe we could use an agent that has potentially lower cardiovascular risk associated with it and give it a shot. Ideally, I would actually like to intensify and add another agent to really, as you said, cytoreduce, perhaps even reduce the disease volume, maybe there would be a lower risk of irradiating adjacent structures if we were able to get things down a little bit. But I would agree 100%. I think that a systemic therapy option would be useful for him if he's willing to try, and we can support him through it.

Geoffrey Sonn: Great. Alicia, you mentioned trying an agent with a lower cardiac risk. So what specific agent would you have in mind and how might you factor in his preferences into deciding what you recommend?

Alicia Morgans: So there has been some recent data with the GnRH antagonist relugolix, and it was compared head-to-head prospectively with a GnRH agonist leuprolide, and it did have about half of the cardiovascular risk. That risk seemed to be reduced most effectively in men who had a history of cardiovascular illness. It is the only oral agent that we have to provide ADT. The good thing is for a patient who wants to stop, it does have a more rapid testosterone recovery than our injectables, or at least in that study, than leuprolide, which took a little bit longer to have testosterone recovery. So the on-off ability and the reduced cardiovascular risk may make this a good option for this patient.

Geoffrey Sonn: Okay, great. Thank you. What do you think about the duration of hormonal therapy for him? Is this going to be something that you would stop after the course of radiation? How long would you continue this? Imagine, so we're looking at something in his pelvis, but then also the inguinal node. How might that change if his disease was elsewhere? Say he had nodes in the supraclavicular or retroperitoneal nodes, would that be any different than what we are seeing here?

Alicia Morgans: Well, if he had much more distant nodes, I think that we would probably be talking about systemic therapy as the primary modality and not talking as much about targeted radiation or metastasis-directed therapy. Although I could be wrong, and I can pass that back to Hillary in a moment.

But I think what we could try because everything at least is relatively within the area of recurrence except that inguinal node, is a duration of ... ideally I would want him to try for two years. The reason is actually really that inguinal node. That concerns me that he may have more distant systemic disease that we just are not picking up, even with this more sensitive modality.

I would settle for a compromise though. I think that six months at a minimum and up to two years, and then a trial off of ADT of all types, including anything we add for intensification to see if we can monitor over time if his PSA remains low, maybe our metastasis-directed therapy, systemic treatment combination, will have eradicated his disease to the extent that it takes a long time to come back, or he never has to deal with it again.

That would be my thought, but there's not a lot of data to support that, I should say. I would also have a conversation besides with the patient, with Hillary, because she is the one who is going to radiate him, and I'm sure she has some preferences.

Hilary Bagshaw: Yeah. So to, I guess, to go back to your kind of point about if he had more distant disease, probably we would be avoiding pelvic radiation. I would agree. Often what I've done in those cases if the person is kind of healthy and young and fit is prefer to start with hormone therapy, and then we could always consolidate later if there was a spot that was growing in spite of the hormone therapy, or just be persistent, maybe consolidate depending how he was tolerating things to perhaps get him off hormone therapy faster or something like that. So I think your point of just working together with your colleagues in medical oncology to kind of come up with a plan you're both comfortable with is important and obviously with the patient too.

Geoffrey Sonn: Okay, great. So it sounds like we are talking about somewhere between six and 24 months of ADT coupled with radiation to the visible disease. Andrei, I wonder, maybe you could speak a little bit towards the results of the CONDOR Trial and to whether this ... because we're directing our treatment towards the known sites of disease ... what confidence do we have that these are his only sites of disease versus what is the chance that he is harboring additional metastasis elsewhere in the body?

Andrei Iagaru: That's a very good question. The CONDOR study showed a very high rate of correlation with the standard of care. It showed high sensitivity, but a lower positive predictive value. The ability to rule out other sites of disease was pretty high. The fact that PSMA is overexpressed in up to 90% of cases gives reassurance. It is not 100%, and that is a reason why our group and others are looking at other targets, such as bombesin receptors for example. Also, thinking a little bit off the cuff, and they are not FDA approved, but one question for Alicia, and one question for Hilary, what about lutetium-177-PSMA? Can that be a part of this conversation once FDA approved? Then Hilary, we just installed a biology-guided radiation therapy device, the RefleXion unit. Can you do multiple metastasectomies with PET-guided radiation therapy?

Hilary Bagshaw: I guess I'll answer that one first. Yeah. So the RefleXion is a great machine. We still do not have the ability to use it for PSMA or prostate-specific PET imaging. I'm hoping in the future that is something that we can do as part of the next trials. So I think that yes, in the future, could we just SBRT all these PET avid sites, that would be ideal. I would still be worried about micrometastatic disease in the other pelvic nodes. So I would probably still favor a more broad approach of radiating the pelvis to a lower dose and then boosting the lymph nodes.

And then lutetium, I agree seems to be a good option. I guess I usually think about it for patients more down the line if they don't really have another option after radiation, but maybe you guys can change my mind about that.

Alicia Morgans: Well, lutetium is intriguing, especially since we see that these are PSMA avid lesions, but t's not approved yet for mCRPC in the basically third-line setting. So I don't think it will be utilized in this type of setting with very low volume hormone-sensitive metastatic disease in the really, really near future. Although there is a trial that has very recently launched, and it is looking at trying to treat people who have metastatic hormone-sensitive disease. I don't think that this patient would necessarily meet the criteria because I think you do have to have disease that is measurable by CT, but it could change ... All of this can change as we start to get data coming in that helps us understand how to best take care of people. And clinical trials are a great way to get access for people if it's not yet approved.

Geoffrey Sonn: Okay. Terrific. I think one other important takeaway from the CONDOR Trial is that while a large proportion of men in this setting of biochemical recurrence do have detectable disease seen on a PSMA PET but not on conventional imaging, it does not necessarily mean that we're seeing all of the sites of disease and that sensitivity is imperfect. So we will learn more, I think, in the coming years, as we try to perform metastasis-directed therapy as to what is the long-term durability and what proportion of these patients actually do harbor other sites of the disease that either don't express PSMA or are just so small that they're not yet visible. So I think that will wrap this up with case number two.