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Jeremie Calais: Hello everyone. Thanks for joining the PSMA PET Academy, organized by UroToday, partnering with the PCF and our great partners, POINT Biopharma and AAA. Today it's my greatest pleasure to present a couple of biochemical recurrence cases and the impact of what PSMA PET can have on radiation therapy planning or treatment management. The two key experts that will discuss these cases with us today are Dr. Michael Morris and Dr. Alberto Briganti.

Michael Morris: My name is Michael Morris. I'm the Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center in New York City.

Alberto Briganti: Thank you. And thank you, Jeremy, for this kind introduction. My name is Alberto Briganti. I'm a full Professor of Urology at The Vita-Salute University San Raffaele in Milan, Italy and I'm responsible for the prostate cancer unit here.

Jeremie Calais: Great. It's great to have such experts with us to discuss a few cases I chose to show here. This is the case of a patient who had surgery in April 2007. The pathology was pT3bN0M0 margin-negative and the Gleason was 4+3 at that time. You can see that the PSA remained undetectable for quite some time, and then rose to 0.2 in 2016. At that time, the patient got another PSMA PET scan, which was negative again. Similarly to the prior case, he got Salvage Radiation Therapy, but this time just to the prostate bed, 72Gy, and no concomitance or adjuvant ADT. Two years later the PSA increased continuously up to 0.6, which triggered another PSMA PET scan at that time. Here is the PSMA PET scan. I'm going to start from the prostate fossa.

You can see also I'm going to show the mid first. The review of the patient...trying to see if there is an obvious lesion. Nothing quite obvious here, but of course it's always very important to scroll to the slides. I adjust a little bit, nothing special. The area of which are the most suspicious of recurrence after surgery in that setting is here. You see the clips, you try to look for some little activity. There is nothing. We look on the side here; maybe we can increase a little bit of sensitivity because the likelihood is more. So I push the SUV scale a little bit, trying to look what this signal here is still the ureter, some urine, we go up... Nothing in the nodes.

So the next thing to look at...here, there is something that is outside of the normal activity. It seems it's in the bone, so let's switch to the bone window. Here you see clearly a lesion in a right rib, just at the basis. I'm not going to show you everything, but at the end that was a single lesion that was discovered in that patient. So at the end you have a patient with BCR after surgery. After Salvage Radiation therapy, PSA is now 0.6 and you have this single rib lesion. What would you do, dear Dr. Morris and Dr. Briganti?

Michael Morris: Alberto, why don't you go first on this one.

Alberto Briganti: There are some considerations in this case, which are kind of interesting and intriguing, in the sense that we have a patient with localized prostate cancer with a kind of favorable natural history. He didn't have any recurrence until 2016 and then he received some additional therapy and now is recurring again. So there are some data which I believe we should take into account regarding the patient, which is age, comorbidity profile of life expectancy, which we don't have in this specific clinical scenario, which I believe needs to be taken into account whenever there is indication or additional therapies in the setting of salvage treatments. Definitely this is a case where I will sit with my nuclear medicine physician to actually look at the characteristics and to have additional data about SUVmax, for example.

In an ideal scenario, which might not be this one, I would also look at which kind of PSMA tracer we used, whether the Gallium-Fluorinate agent, which I believe sometimes especially for the 9071007 has some false positive uptakes in the reads. Then, let's put the clinical case or the clinical situation, which these patients had high suspicion of single metastasis in the [inaudible 00:05:44]. This is a long, natural history, prostate cancer recurrence. The patient's already received Salvage Radiation Therapy and the decision will be to counsel the patients on whether undergoing metastasis-directed therapy in this specific clinical setting, whether this is feasible using a force SBRT. If patient has a long life-expectancy and good clinical profile, and if there is a prospective protocol at the center where the patient is treated and we have the confirmation by our [inaudible 00:06:25] physician that is highly suspicious recurrent disease, then I will counsel the patient about the possibility of undergoing metastasis-directed therapy, directed to this single rib lesion.

In this case, I will definitely use concomitant ADT as a short-term adjuvant therapy to SBRT to the rib, which we do nowadays as almost the standard of care whenever we do SBRT for recurrent disease. So there are different considerations to be done and if we eventually end up with a patient with good comorbidity profile, long life-expectancy and a highly suspicious lesion like this, I would consider the patients for MDT plus short-term ADT.

Michael Morris: Very good. I think the only thing I might add onto Alberto's comprehensive answer is first, if this is oligoprogressive disease, then there is data in STOMP and ORIOLE to do SBRT without ADT. I, like Alberto, feel uncomfortable with that approach because this patient has metachronous, low-volume metastatic disease. And we know from many trials that patients, regardless of whether they have synchronous or metachronous metastatic disease, high-volume or low-volume, benefit from, in terms of life-prolongation, from some exposure to ADT. And I would add also an ARSi. You can't get better quality data for what we should be giving patients with metastatic disease, of all types and all presentations, being ADT and an ARSi. The issue is, in terms of the radiation, I would feel uncomfortable committing this man who has such a low volume of disease to a lifelong ADT and an ARSi.

I agree with Alberto that there's a role for consolidative radiation therapy for this isolated area and would thereby give him a limited course of ADT and an ARSi with stereotactic RT, with the intent of both giving him a life-prolonging therapy regimen in conjunction, and which probably will be working synergistically with the radiation component, and then taking him off all therapy and waiting for the next evidence of relapse to make a decision about longer-term ADT and an ARSi. I think also now that he is presented with metastatic disease, one needs to think about genomic profiling, which would be standard of care for all men who have metastatic prostate cancer. So we shouldn't forget about the genomic profiling for longer-term planning as well.

Jeremie Calais: Okay. Thank you very much for this insight. So more information following what you just said, the patient was young, a 66 year old; pretty active. Let's look at the SUV. It's a great comment, you're completely right, Dr. Briganti. The read is really the most common false positive finding you can have on a PSMA PET scan, which induced, in many cases, presumably wrong management decision. So you can see here the SUVmax is 3.4, which is still in the range where you have some overlap between benign and malignant lesions. But you can see that the focality of the pattern of the uptake here is...there. You have this focal pattern completely differentiating from the surrounding background. You do have some sclerosis; no lytic lesion, no other CT pattern that could evoke something else. So you'd really have the classical sclerosis that you see on the prostate cancer bone metastasis.

So at the end, this was considered to be a bone metastasis. The patient received radiation therapy only; no ADT, no systemic therapy agent here. Luckily, for sure it wouldn't work like that all the time. But in that case, four years later, the PSA is still undetectable. So this patient really benefited from the PSMA PET scan-based salvage or oligometastatic directed therapy. But, you're completely right. It doesn't work like that in all these cases. I'd just like to show this great story. Patient is pretty happy about that as you can guess.

Michael Morris: The only thing I would point out, Jeremy, is twofold. First, I think that if truly you felt ambiguous about the PET interpretation, you could always just follow the patient. This isn't a curable situation and if you felt like you needed a few more months to repeat the PET, you could. Second I'd just be careful about saying that the patient benefited from this. 'Benefited' is an interesting word. You made the lesion go down and you made the PSA go down. But I'd just be careful that the patient has yet to receive any known life-prolonging therapy. So, delaying life-prolonging therapy actually we don't know is beneficial. But you did make everyone feel better by making the lesion go away. But be careful about saying that we benefited him. We don't know that.

Jeremie Calais: You're right, yes. Thank you very much for calling this out. It's exactly the point.