Charles Ryan: Hello from APCCC 2019 in Basel, Switzerland. I'm delighted to be joined by two colleagues, Piet Ost from Ghent, Belgium and Felix Feng from San Francisco, California where they're both radiation oncologists. We've been having a conversation about recurrent disease after radiation therapy and the role of the radiation oncologist in that setting. It's a controversial issue. This is a conference where we should bring up controversies and decide on consensus. Felix, in your mind right now, what is the consensus on what we should be doing in a patient who has received primary therapy with radiation then develops a recurrence.

Felix Feng: I think the first thing to think about is how to work up these patients. There's a much different approach to treating patients who have a local recurrence without any evidence of other disease versus patients who have regional distant metastasis. Key to that workup is imaging. In the context of patients who we think might be good candidates for for local therapy in this context, we would do an MRI potentially with a biopsy via ultrasound, and then we would add onto that conventional bone imaging, either a bone scan or a PET CT, PET MRI to rule out distant disease and so forth.

Charles Ryan: I look at this as the problem of you don't know what you don't know, right? You can biopsy the prostate. You can find recurrent disease. That's all well and good, but what you don't know is that the systemic circulation is free of disease. You're really radiating on faith or treating on faith that what you are treating is the entirety of the tumor.

Felix Feng: Absolutely. Just because you can't see something on imaging doesn't mean it's there or it's not... I mean, that's there. But I think the point to think about is that there have been a number of studies now that have shown that patients who get treated with radiation upfront, if they have a positive biopsy after treatment at the time of PSA recurrence, those patients have far worse outcomes than patients who don't have positive biopsies. Clearly that local recurrence is contributing to poor outcomes down the road and clearly that's why the rationale is there that we should be trying to address that local recurrence. That can be addressed with salvage brachytherapy, salvage prostatectomy, cryotherapy, high intensity focused ultrasound. Right now we don't have any data to suggest that one of these is better than another right approach.

Charles Ryan: Right. We clearly need studies to address this population, but one approach might be to say we know that there's a local recurrence, as you say, the local recurrence is the fountain of tumor cells going to the rest of the body, so we'll probably need to think about systemic therapy as part of a future study that's conducted in that area.

Felix Feng: Absolutely.

Charles Ryan: For the time being, we'll leave it at that and say that focal radiotherapy or radiotherapy after primary radiation remains a bit controversial, investigational perhaps, but is associated with worse outcomes when local recurrence does occur.

Felix Feng: I think that's a fair statement.

Charles Ryan: Okay, good. I'm going to transition and I want to talk a little bit about metastasis-directed therapy. There's a lot of this going on. You've been the one really, I guess, the world leader in developing data around this point. What does your data suggest is the role of metastasis-directed therapy at this time?

Piet Ost: Well, we started already in 2005. We started out with FDG-PET detecting recurrences early. We transitioned to COLA, and we're now with PSMA. But over a time span of almost a decade, I must admit that we made a lot of progress technically, but the evidence we still have to wait. There are now some early Phase II trials indicating that at least there's a better progression-free survival when you go for SBRT as compared to no treatment at all.

Charles Ryan: Right.

Piet Ost: I think now it's the time to take that next step. Because if you look at SBRT only, we see that a lot of patients, approximately 50%, will fail within one year and that's a fairly high rate. It appears that even with this novel sensitive imaging, a lot of patients appear to fail. I think by adding a systemic drug, doesn't matter probably what it is, as long as you're thinking of it in a smart way. It can be radium. It can be ADT. It can be one of the novel antiandrogen receptor inhibitors. I think there's a lot of potential to explore. But the question is what's the ideal endpoint there? That's also if you want to go for survival, it will take us up to 20 years to find something unless maybe we take a STAMPEDE approach. But yeah.

Charles Ryan: I'll tell you as a medical oncologist, I've sent patients for a metastasis-directed therapy over the course of a number of years. My experience ranges from seeing... I think one case I can clearly remember where I think the patient was cured to other cases where we radiated one or two metastatic sites only to see that the next PSA was much higher than the previous one. In fact, suggesting that it did no good. I think as a medical oncologist, my perspective would be to say, "If you can show me the type of patient who could be cured or close to cure it, if you want to call it that, meaning very late recurrence or something like that, with the metastasis-directed therapy, that would be worthwhile." But I think there's a little bit of a lumping problem here now where all of the... We're sort of looking at all different types of disease states and things like that.

Felix Feng: Chuck, I'm going to be a little provocative. I'm going to step in here. You're a medical oncologist, and we do a number... Your field, medical oncology, does a number of studies where if something gives a 10 to 20% benefit, you act upon...

Charles Ryan: A hazard ratio of .75 is the new drug.

Felix Feng: Right. Absolutely. What that actually means is that you overtreat a number of patients to benefit some. Right? That's in the context of prolonging life.

Charles Ryan: Right.

Felix Feng: Theoretically, there's a subset of patients with a local metastatic disease that potentially are curable. It might be a small percent, but what Piet has shown in his studies is that it might be 10 to 20% of patients. Why the hesitance in overtreating patients to try to cure a 10 to 20% when we clearly overtreat many patients in the metastatic sense?

Charles Ryan: Well, I want to hear your thought.

Piet Ost: One of the problems is in that biochemical recurrence setting, it appears to be that early systemic drugs like ADT from the TOAD trial isn't improving survival as compared to delayed ADT. I think we can irradiate a proportion of patients to get those 30%, which have a very long time of disease, time of recurrence, with only one intervention. But we have to counsel our patients correctly. But I do think if you want to increase that from 30% maybe to 60%, that we have to add probably short duration of, for example, ADT like we do in salvage or in primary radiotherapy. That smart combinations I think will make the big push.

Charles Ryan: I think you point out a potential sort of dividing line here. One would be let's go for cure. Let's add ADT. Let's radiate the metastasis, right? The other is you don't want to be on ADT. I can radiate your two metastases today and maybe we'll delay your ADT for a year. Those are two very different paths. One is accepting the fact that systemic therapy is coming, lifelong therapy is coming, and that this disease is not curable, and the other is going for the cure. I think both are acceptable. My previous point was also to be provocative, right? But I think we should clearly define that as two different, sort of, paths.

Piet Ost: Yeah, that's correct. There's a lot of unknowns. What's that ideal number? What's the ideal imaging? What's the ideal timing? We're doing our homework, and we're doing the trials now. In the US, several trials are running. In Europe, several trials. In Australia, several trials are running, Phase II's, Phase III's. I think we'll be getting there. Some of the trials will pull different histologies, not only prostate, and there I think those are very interesting from radiation oncology field. Interesting to see that even if you pull all these histologies, the net effect of adding SBRT to a standard of care seems to improve survival. Those are still early data. But if we can confirm that in a randomized Phase III, will we still be needing a specific trial in every subset of cancer types? I'm not sure. I think it might make it as a standard of care if you're able to in those bigger, more histology agnostic trials make a difference.

Charles Ryan: Right. Back to the imaging issue, do you think you've optimized the imaging that would lead to metastasis-directed therapy now with PSMA PET?

Piet Ost: I don't think so. One of issues we have now is we image patients with PSMA, but we don't see anything on CT. Sometimes you don't even see anything on MRI, so then you have spots. As de Bono said, it's not all-

Charles Ryan: Not all that glitters is gold.

Piet Ost: That's one of the issues we've been facing as well. We see a lot of patients. We say, "Well, we see something on your PET. Not sure it's cancer," then the question comes back, "Then what is it?", "I'm not sure, but I can't target it".

Charles Ryan: Yes.

Piet Ost: Same with nodes. We've now seen nodes up to two millimeters. If I put them under my cone beam CT, which we use to guide our treatment, we don't see it. We are getting in a space-

Charles Ryan: We've run into cases like that where-

Piet Ost: ...difficult to manage.

Felix Feng: Chuck and I treated patients together for a number of years, and I would say we also have the opposite side, which is if you put it into perspective, if you have a cubic centimeter of cancer on a CAT scan, that's probably a billion cancer cells present. Let's just say that PSMA PET is a thousand times better. Okay? What that still means is there's a hundred thousand cells that are required to see something on PSMA PET. If you have less than a hundred thousand cells, does that mean that there's no cancer there or not? I've had people come to me and say, "Well, listen, we now have a patient who has a PSA recurrence. The PSMA PET is negative, so maybe we shouldn't treat because there's nothing there." Just not realizing that salvage radiation let's say to the prostate bed has been the standard of care for quite some time now is curative in 40% of patients, give or take, and we shouldn't be throwing out the baby with the bathwater here.

Charles Ryan: The typical patient who has a radical prostatectomy is now presented for salvage radiation therapy let's say, has a negative PSMA PET. Many of those patients will still have disease in the pelvis only. This is the big question that I face with these patients is, again, we don't know if it's only in the pelvis.

Piet Ost: The dominant relapse pattern is local regional. We know that from the different studies we've done. Why not give a treatment which has fairly low toxicity and still go for the cure?

Charles Ryan: Right.

Piet Ost: There's one series from Lewis Emmett showing that if your PSMA PET is negative and you just do salvage radiotherapy, you've got an 85% of declining PSA. That shows you that PSMA is not sensitive enough to detect the local recurrence. The message that negative PSMA then we should forgo on salvage radiotherapy is completely wrong.

Charles Ryan: Right.

Piet Ost: That's a message I think is very important.

Charles Ryan: In fact, the patients with low Gleason scores, positive surgical margins, sort of favorable features, will have pretty good outcomes with salvage radiation therapy-

Piet Ost: Correct.

Charles Ryan: ...Independent of PSMA PET.

Piet Ost: That's it.

Charles Ryan: Great. Well, I want to congratulate you both for great presentations here for helping us to sort of clarify what's going on in the world in this space and for leading the field in helping us to define all of these approaches. Thank you very much for joining us today.

Piet Ost: Thanks a lot.

Felix Feng: Thank you, Chuck.

Piet Ost: Thank you for having us.