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Charles Ryan: I'm joined by my friend and colleague, Fred Saad, Professor and Chief of Urology and Director of GU Oncology at the University of Montreal Hospital Center. Fred, always a pleasure to chat with you.

Fred Saad: Always a pleasure.

Charles Ryan: Today we're going to talk about the full spectrum of CRPC. And it's really interesting, a little bit over a decade ago we talked about CRPC as a disease where there were symptomatic patients and asymptomatic patients as if that was the only nuance that mattered. And then when we saw the development of abiraterone and enzalutamide and we now started integrating these therapies into earlier CRPC, but it was always about metastatic CRPC. And so now we've brought in the non-metastatic CRPC. So I guess my first question for you is, as you sit back and look at this spectrum of development, what do you think is the optimal way for the clinician to frame this clinical entity that we call CRPC?

Fred Saad: So the entity of CRPC is becoming more and more intriguing. Exactly like you're saying, we used to dichotomize even pre and post-docetaxel is if the patients are dependent on whether they got chemo or not. And that was an easy thing for designing clinical trials. And now I think we're starting to become ... Looking at this disease more intelligently and trying and understand the biology of the disease and obviously, the low hanging fruit is PSA. And PSA doubling time as a reflection of the biology of the disease. So we've gotten to the non-metastatic CRPC setting based on what we consider high-risk patients based on their PSA doubling time and high risk by meaning time to becoming metastatic or dying of the disease. And so the trials, there are now three randomized trials with AR-targeted therapies that have shown very significant improvements.

Apalutamide, enzalutamide, and darolutamide. Then if we take the high-risk population, rapid doubling time and we introduce those therapies, we significantly delay the time for metastatic disease. And I think we more effectively treat the disease, not only delaying a radiographic change, but I think we actually make it a bigger difference in addressing the disease itself.

And why I say that is if you look at a year trial with abiraterone or the trials with enzalutamide, patients who went onto those trials were metastatic, an obvious metastatic disease, the time to PSA failure, which was the first sign that they're starting to resist occurred in less than a year on average. Now when you look at these patients who are CRPC, but lower volume metastatic disease because we don't even see them on conventional aging, it's taking in the range of three years and more before PSA starts to rise.

So we seem to have a bigger impact in terms of response but also the length of time that they respond before they become resistant to these therapies. And so I think it is critically important that the high-risk patient who's likely to become metastatic and suffer from the disease be treated really early. And we understood that in the metastatic disease setting where your own study showed that if you took patients who are clearly asymptomatic, lower PSA levels, lower alk phos, they seem to have the greatest benefit in overall survival. So it's a natural progression to go backward.

And I'd actually even go a little bit, even more controversial. I actually believe some metastatic patients with slow rising PSA are less worrisome than the non-metastatic with very rapidly rising PSA, so this dichotomy ... I see the mets, or I don't see the mets. I think we have to change the way we view these patients.

Charles Ryan: Let me ask you a couple of maybe provocative questions, maybe not so provocative. Is it ever acceptable for a clinician to not treat a CRPC patient until he gets pain? In other words to wait to pain?

Fred Saad: No.

Charles Ryan: Good. I agree.

Fred Saad: I mean, there are always exceptions to every rule.

Charles Ryan: But people do it. People were doing it, people were doing it a while ago. And I think, let's say we've put that one to bed, right?

Fred Saad: Yeah.

Charles Ryan: Okay. So my next provocative question is-

Fred Saad: But I'd say we haven't completely put it to bed because I was on a guidelines committee with very prestigious guidelines that were saying we don't need to image the non-metastatic because we don't really need to treat until it becomes symptomatic. So they're not saying I wait until symptoms but I don't really investigate until they're symptomatic because I don't really know it makes a difference.

Charles Ryan: I think we've put this to bed maybe in North America. I think there's some controversy around the world where resources may be limited. Other things about waiting, but I think a clinician should not say to a patient, look you feel good. Go come back when you have pain and we'll treat your disease. For two reasons. One we're waiting for the patient to suffer. And two we know even from the chemotherapy studies that the therapies tend to be less efficacious when administered to a patient with pain and that came out in the docetaxel studies and it certainly came out in the abiraterone studies. But let me follow up with another question. Is it ever acceptable for you to observe a patient with metastatic CRPC who is asymptomatic and to simply say, well, we'll defer treatment for three months or six months or when we see those patients, should we be starting enzalutamide and abiraterone, et cetera?

Fred Saad: So that's probably a little bit more nuanced. And I would say for the overall patient who is clearly metastatic on conventional imaging CRPC, I don't need to wait long. I mean the enzalutamide study showed us because we had a pure placebo arm that the average patient will progress radiographically within four months.
So if we're waiting for radiographic evidence of progression to start therapy, we're not going to save that much time and we might lose valuable efficacy by waiting until they are more burdened with metastatic disease.

Charles Ryan: So waiting for symptoms is probably not acceptable. Waiting for radiographic progression may be acceptable. Right? I mean in some cases, but you're saying you have other parameters that you can follow before rising PSA rates and things like that. And so the third question then is, is it ever acceptable to not treat a non-metastatic CRPC patient now that we have all these agents available and all these studies showing that it benefits them?

Fred Saad: So this is where I think the discussion becomes more interesting. I think for the first time in castration resistance, competing risks of death become important.

Charles Ryan: Great point.

Fred Saad: I mean, so we included patients who were 95 years old in those trials, right? And when you're nonmetastatic, the biology of the disease means you might live several years before actually dying of the disease. And if I introduce effective therapies, they're going to be effective. And so the cause of death may no longer be prostate cancer. So did the drug contribute to the death of the patient or did I just control it so well like with ADT that they died of something else? And I wouldn't want people to think that these drugs kill patients. And so I think for the first time we actually have to start thinking of survival probabilities based on age, comorbidities to make the decision of who I treat and who I don't treat it in a non-metastatic setting because their survivals are much longer than the metastatic side.

Charles Ryan: I think that's a great point. I would also make the point that a lot of us who are out there treating patients maybe aren't so well versed in how to predict survival using other comorbid conditions. I mean when we start looking at the list of medications, we start to look at the other diagnoses and we sort of make a broad assumption about this person's survival. But there are tools that you can do this and there are functional tests that one can do a to assess somebody's survival. But I think you're right, especially in the non-metastatic CRPC setting where we're beginning to get into the situation where we need to make sure we're not just treating the PSA, we're treating the patient and we're looking at the competing risks of morbidity and death I should say.

Fred Saad: And in the field of prostate cancer this has been a challenge all the time. Who do we screen? Who do we treat for localized disease? For radical prostatectomy, we've put the bar at 15 years of survival to be worth doing it. So we have ... But I think here it's easier to figure out who's going to live five years and who's not. It's probably easier ... But the effort has to be made so that we don't introduce therapies that are costly in patients who are unlikely to benefit. But for the average patient who comes into the clinic, walking, who's well at home, the majority of those patients deserve to be treated if they are in the higher risk population.

Charles Ryan: So my final question then is, a clinical scenario that's been on my mind, which is with all of these new therapies that we're using early, and we do that with such optimism now. It's actually great to see a patient with a relatively low PSA and three bone metastasis and say, oh, we've got all these options and then you put them on enzalutamide or abiraterone or whatever the drug may be and they have a good response.

And then you find yourself a year and a half, maybe two years later, where they've enjoyed good quality of life. You find yourself two years later when they become resistant to those therapies saying, oh, now what? And the question is not every patient ... We're back to the situation where we were in 2003 and 2004, not every patient's the docetaxel patient. They've lived longer because of the early stuff we've done. But what do we do in those abiraterone enzalutamide resistant patients that we treated early, who now may still look really good? They may have a low burden of disease, they may have good performance status, but the treatments that we have are going to not look as effective as they once did.

Fred Saad: And I think that's the reason why research continues today as intensely as it was 15 years, if not more. Is that we're actually now not focusing so much on drugs but on patients and disease biology. And the way we're trying to do trials now is trying to understand what we're actually treating because we've actually created something different. That cancer that we started treatment in that was treatment naive now has progressed through first line of therapy, has obviously changed in biology. And so some patients, the best possible choice is going to be chemotherapy. Who are those patients? It would be nice to know before we actually get into the chemo. Some patients are going to benefit greatly from PARP inhibitors. I've got patients who've been on for three years that are responding beautifully. Some might actually respond to immunotherapy. They're the minority. But who are they? And some patients might actually benefit from going from one AR-targeted therapy to another.

And understanding who those patients are, there might be a 15% that their AR is unmutated and responsive to another line of ... And so we're doing those kinds of things in the NCIC like you're doing in many others.  If we're actually taking circulating DNA and trying to analyze what mutation is there and is there an adequate drug for that patient.

Charles Ryan: So you've got your DNA repair channel, we've probably got the neuroendocrine channel, we're going to probably have a small but maybe an exploitable immunotherapy channel. We've got the AR-V7 channel, which says this is probably a patient who would benefit from chemotherapy over all of their choices. And we've got the palliative panel, a channel where we may be using, for example, radium as a therapy with both palliative intent and life-prolonging intent.

Fred Saad: Yeah, I think it's fascinating and patients are forcing us to make those intelligent decisions with them.

And we say with them because the patients have a big say and I make a big distinction of the patient who's still feeling well, just PSA rising imaging pretty stable or slight progression. I don't pull the plug too early and that's sometimes a mistake to pull the plug too early. But as soon as PSA starts to rise, we have to start thinking.

Charles Ryan: As a researcher at a university, I'm sure you feel this as well. I feel the pressure coming from the patients. I feel the pressure coming from the laboratories as well, which is really fun, which is we've got these incredible laboratory scientists all over the world telling us about new drug targets, new mechanisms of disease progression and new subtypes of the disease. And then we're faced with identifying who those patients are and trying to develop those therapies. So it remains an exciting time. It's always great to catch up with you at these meetings and to hear what's on your mind.

Thanks again for joining me today, Fred.

Fred Saad: Always a pleasure.