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Charles Ryan: As usual, there's a lot going on in our field at ASCO GU 2019 we now have a new agent, perhaps, for non-metastatic CRPC (nmCRPC), which has been a topic of great interest over the last couple of years. I want to dive into that topic with you.

So if you could just please give us an overview of the three agents so far that have demonstrated benefit compared to placebo in that setting.

Fred Saad: Okay, so, you know, you and I have been involved in trying to do something in non-metastatic CRPC for a long time and we've had several trials that have all either failed or not been impressive enough to make a change. But we have learned something. We've learned that PSA doubling time is probably the best predictor of who's really at risk of progressing to a metastatic state quickly and even dying of the disease in a short amount of time.

So that was the basis of these three trials that used the same mechanism of action targeting the androgen receptor, which makes perfect sense, which we know from the enzalutamide era, that this is an extremely effective target, leads to better survivals, longer time to progression of metastatic disease. 

And what we've also learned from those trials is that it looks like earlier is more effective. Patients respond better. They have more chance of complete responses and they respond for a longer amount of time and it takes a lot longer to develop resistance. So, based on that it made sense to look at this non-metastatic, castration-resistant setting in a high risk population that we know are gonna do poorly in a relatively short amount of time.

Charles Ryan: Who's the typical patient? We'll get into the actual drugs in a second, but who is the typical patient who has non-metastatic CRPC? Is this a person for example who had a radical prostatectomy and then got put on ADT for his rising PSA? Or, you know, what's the pattern there?

Fred Saad: Yeah, so in North America, in Europe, especially several countries of Western Europe, and Australia, we've taken an approach where we realized that patients who got local therapy or didn't get any therapy at all because it was felt it was a locally advanced disease and were put on ADT, that when they failed, these patients were gonna do poorly. And we can always discuss, is there an indication to treat a non-metastatic patient, and I would say yes. In a patient who's high risk, rapid PSA doubling time, high PSA, we should do something because we have data that if you wait until they're metastatic, they don't do as well.

So that patient population is exactly what you said. A lot of them are patients treated with radiation therapy and have failed. So, a lot of those patients treated with radiation are actually high risk, high volume, localized disease that eventually fail and then get ADT as a salvage kind of therapy. With surgery they can also fail, but, you know, the majority of those patients would probably get radiation and then fail and go on to ADT. 

So that is a population of patients that we were once accused of creating a state of CRPC.

Charles Ryan: It's an iatrogenic clinical state.

Fred Saad: But I would argue that we did a lot more good than harm when we treated patients at high risk.

Charles Ryan: Yeah. You know, for a patient who's had radiation and then goes on to ADT and then develops non-metastatic CRPC, there's always the implication that he has disease confined to the prostate at this point, whereas the person who's had a radical prostatectomy gets on ADT and then develops non-metastatic CRPC, it's presumed that he has an occult burden of systemic disease that has not yet amounted to a three dimensional metastatic focus.

Fred Saad: Right. But I would argue that even in the patient who got radiation, yes it could be that there's local recurrence, but I think the biology of the disease is closely linked to the PSA kinetics. And a patient who has rapid PSA kinetics is likely to be harboring high risk disease that is micrometastatic. And even if it's localized to the prostate based on, you know, the new imaging with PSMA, it's still unattainable to retreat the local disease- Because the biology just doesn't lend itself to long term responses.

I think looking at PSA doubling time, and when we talk about the high risk patient, we did a populational based study, and it represents about 30% of those non-metastatic CRPC. So we're really targeting those high risk patients with these new agents, because those are the ones that are the most at risk of developing metastases and actually dying of the disease.

Charles Ryan: Okay, so you're faced with a patient who has non-metastatic CRPC. The PSA's low but it's rising. The patient is well. Why should you treat somebody? Why not wait for them to develop metastatic disease? They don't have symptoms because they don't have metastases. There's a cost to these agents in terms of the toxicity and certainly the financial burden. So make the case that we should be treating non-metastatic CRPC.

Fred Saad: So I base the case on one of the studies that you led, 302. I base it on PREVAIL, which is the enzalutamide study in the chemo-naïve setting. I base it on TERRAIN, where we had really early metastatic CRPC, not even having failed bicalutamide, secondary hormonal. And every time you look at the analysis closely, you realize the ones that benefited the most were the ones that had the least metastatic burden, lowest PSAs. They responded better and for a longer amount of time.

So the next logical step is to say, "Why don't we take the micro-metastatic state?" And when we talk about non-metastatic, we're talking about conventional imaging.
And you and I know that if we had better imaging, we would find something somewhere in those patients. So we're just taking that metastatic state and bringing it to a state that is probably still micro-metastatic and we're introducing effective therapies and we're seeing it. The time it takes for PSA to rise in that state of non-metastatic CRPC is in the range of over three years. Whereas whether we look at PREVAIL, 302, it's more in the range of 12 to 18 months and they start failing already. They're already starting to develop resistance. And I think it's easy to understand the more you have tumor burden the more likelihood you have a clone that is hormone-insensitive and is going to manifest itself.

Charles Ryan: I think, if I could restate what you said, it's not just that you're treating patients earlier but that you get more mileage, you get more effectiveness out of the drug, because the disease is less complicated. In a way-

Fred Saad: Absolutely. And an attempt to look at that was this concept that's sometimes misunderstood is the PFS2. And PFS2 is really an attempt to say, "Does it really make a difference, starting early in the non-metastatic CRPC state, or waiting until early metastatic disease?" And when we did the PFS2 analysis reported over a year ago and now update with an extra year, those curves stay completely separate and are not even coming close to coming together.

So really, every attempt we have in early metastatic disease doesn't allow us to catch up to the ones that we started when they were still so-called micro-metastatic or non-metastatic on conventional imaging.

Charles Ryan: Right. So we have probably three agents available: apalutamide, enzalutamide, darolutamide, I think a reasonable expectation that it will become available to those of us in North America, perhaps worldwide. I'll also just add abiraterone has been studied in this setting but not in a randomized trial. So which agent should we be using in our patients with non-metastatic CRPC?

Fred Saad: Surprisingly, we look at those three studies with the AR-targeted therapy that had a placebo-controlled and the study that you led with abiraterone and they're all showing that you respond for so much longer. So the concept of targeting the AR makes perfect sense. We're seeing really significant improvements in terms of time to appearance of metastases and we're seeing a much longer time that you're responding. 

So, I think the concept, the bottom line, is: Targeting the androgen receptor makes perfect sense. My preference is with a pure AR antagonist because you avoid the prednisone issue for so long because patients will be on for a long time, even much longer than the metastatic hormone-sensitive state, which is a serious disease that progresses much faster to death.

Charles Ryan: Although with the abiraterone study we used 5 mg of prednisone. And actually we have people, you know, we're still following on that study four years out.

Fred Saad: Exactly. So they're on for a long time. So, you know, I think they're probably equivalent; it would be probably very hard to show a difference. But if you can avoid the prednisone all together-

I think there is an advantage in patients if they are going to be on for four, five years. But, you know, some people say, "Oh, that's four or five years of extra therapy."

And that's not true, because the placebo arm actually progressed to a metastatic state in 14 to 16 months, so it's actually about an extra year of therapy for a much bigger bang for your buck like you said. And so I think it really does make a difference starting early in the high risk population. 

Low risk, totally different thing. I wouldn't start a patient with these agents in a low risk, but I think that would be a perfectly good population to do a PSMA and see is there an oligometastatic disease where that PSA's coming from with slow kinetics, may be amenable to radiation and would be a nice clinical trial to do, take low risk patients and see: Does outcome change when we delay further therapy?

Charles Ryan: I believe there are some studies that are gonna take that approach, which is identified lesions through PSMA pet, radiate them if they're oligometastatic with and without apalutamide or enzalutamide or therapy like that. So to look at the combined effects of treating the small burden of disease that is evident.

Fred Saad: But I wouldn't do a PSMA in a patient with a rapid PSA doubling time. I don't think they're gonna really benefit from getting spot radiation.

Charles Ryan: Systemic disease, yeah.

Fred Saad: And I actually worry that we might be harming those patients.

Charles Ryan:I agree too. So that's why we need to do research on this, because you're right. Why take the time and effort and cost of treating somebody with a focal modality when they have a systemic disease? And I think that as you hinted at, there's a cut off somewhere where there are probably low risk patients who may benefit from radiation, maybe they don't even need the drug, and then there are patients who are high risk and won't benefit because it's systemic.

So my question is: When you say "high risk," what do you mean? What are your numbers?

Fred Saad: Well look, I mean, I think we took the cut off of 10 months or less as being considered high risk. And obviously, it's a gradation. So, if you're at 4 months doubling time, you're much higher risk than at 10 months. In the studies when we did the forest plots, they all benefited, whether you were between zero and 6 months or 6 to 10 months. But obviously, the event rates are lower between 6 and 10 months. So, when they're between 6 and 10 months, I actually look at comorbidities, age, because then you have a competing risk of death.  For the first time in CRPC, we're actually interested in competing for risk of death.

Charles Ryan: Right, that's a good point.

Fred Saad: Because, you know, we had some patients that were 95 years old that came into the study. So, at a certain point we have to start wondering are they likely to die of something else before they actually- and those patients I might consider just watching them. 

And I think this was an FDA obligation to look at only PSA doubling time. But absolute PSA is important.

Fred Saad: And when you're above 25, it's as bad as a PSA doubling time of less than 6 months. So you have to start combining PSA absolute value, PSA doubling time, obviously the most important, but then after that looking at the patient and trying to decide who is most likely to benefit. And I would avoid waiting until the metastatic setting sets in.

Because whether we like it or not, the clinical trial, we're imaging every 4 months. None of us will do that in the real world. So we miss sometimes windows of opportunity of intervening early.

Charles Ryan: Yeah, I've lectured before and you've probably heard me talk about the three Ps of our goals of therapy in CRPC, which is to preserve and prevent and prolong. And, you know, I think the non-metastatic setting is an opportunity where we are preserving the absence of metastasis, which has value. It's not a good thing to have a metastatic cancer. We're preventing the complications of metastatic disease and we're prolonging the time to metastasis and likely prolonging life in those cases as well.

Charles Ryan: Any other last thoughts on the whole non-metastatic space?

Fred Saad: So, you know, sometimes I hear the argument, and we used to hear it even in the metastatic state: If you do this, they're gonna be less responsive to therapies later. And I wonder, well, why would you withhold effective therapies early and make a big difference down the road because you're worried about creating resistance that's gonna be harder to treat. But that resistance is gonna occur so much later than when you wait too long.

Charles Ryan: I still get that question. If you treat early, isn't it gonna be more aggressive at the end? Well, but, you know, living longer is generally a good thing, that's sort of the goals of therapy, and no study has ever proven that the LATITUDE and the CHAARTED studies all proved that even when people develop CRPC they still had a good prognosis for the CRPC that they had. I mean, they still were able to be treated with other modalities.

Fred Saad: But they always lived less than the ones who started up front. So I think the upfront is an opportunity of not missing the boat for the windows of opportunity, and that's gonna be our next generation of clinical trials, is what we do with these patients. Yeah, we are gonna create clones that are more resistant, but I think we're gonna be more intelligent in how we actually approach those patients and personalize our approach to treating those patients.

Edited By: Mary Ann Johnston, Pharm. D, Digital Science Press,Inc.