M0 CRPC - Early Treatment Leading to Favorable Outcomes - Fred Saad.

(Length of Discussion: 16 min)

Fred Saad and Alicia Morgans discuss results from A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN) and Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (PROSPER), as well as the endpoint of metastases free survival (MFS).  It is exciting that early treatment in the M0 CRPC patients is leading to favorable outcomes.

Biographies:
Fred Saad, MD. FRCS, is Professor and Chief of Urology and Director of GU Oncology at the University of Montreal Hospital Centers (CHUM). He holds the U of M Endowed Chair in Prostate Cancer Research and is Director of the molecular oncology research lab in Prostate Cancer. He is the past Chair of the National Cancer Institute of Canada G-U Group and the Canadian Urologic Oncology Group. Dr. Saad has been involved in most of the important clinical trials in advanced prostate cancer over the last 20 years and presently sits on 7 steering committees of international clinical trials. In 2014 he received the lifetime achievement award for research from the CHUM Research Center.

Alicia Morgans, MD, MPH. 



Read the full video transcript

Dr. Alicia Morgans: Hi, and welcome to another recording from EAU 2018. We have Dr. Fred Saad with us today. He's Professor and Chair of Urology at the University of Montreal. Thanks so much for being here with us today.

Dr. Fred Saad: It's a pleasure. 

Dr. Alicia Morgans: Wonderful. I think there are many things that we could talk about, and always are when we meet, but I really wanted to focus today on this new data, the M0 CRPC data, that I think has really shaken things up and I'd love to hear your thoughts on it.

Dr. Fred Saad: Yeah. Well, I agree. I mean, I think it's one of the most exciting things that we've had in the past few years. I mean, obviously treating metastatic CRPC with chemo, and then with drugs like Abiraterone and Enzalutamide, have been tremendous. But we've always wondered, what can we do more? I think many of us have been convinced that even in the metastatic setting, treating early is better than waiting until patients are more volume metastatic disease, or symptomatic, with the hormonal approach. The next logical step would be to take patients that are non-metastatic, castration-resistant, where all of us would really assume that in those high-risk patients they have micro-metastatic disease, so what better setting to prove that starting early makes a big difference? I think SPARTAN and PROSPER really demonstrate that early treatment leads to tremendously favorable outcomes. 

Dr. Alicia Morgans: Speaking of outcomes, the outcome of interest was really this metastasis-free survival, which in the United States at least, is really kind of a novel endpoint, or at least a novel primary endpoint, one that we can rely on in terms of FDA approval. What does this endpoint mean and how do you think about the importance? Is it an important endpoint to you?

Dr. Fred Saad: Well, I think it's an extremely important endpoint. Obviously, I think many of us would believe that if we had only that endpoint without any other signals that the treatment is making a definite effect on the disease, we'd all be disappointed, because clearly treating with an active agent compared to a placebo, we all expected that the metastasis-free survival endpoint would be positive. To what extent it's positive, is really what's impressive. I mean, having an over 70% improvement in MFS, which means almost two years of delay of appearance of metastatic disease, and patients that are at high-risk of becoming metastatic is, I think, tremendously important. 

If I push it to the next limit, I was saying that I think patients who are non-metastatic but high-risk, rapid PSA doubling times, when we put patients on study, many of those patients that we screened were actually screen-fails, because we found metastasis. By conventional imaging, they're non-metastatic, but if we had more precise imaging, I assume that many of those patients were actually metastatic, but to a low volume. MFS, to me, in that patient population is actually almost like a radiographic progression-free survival. We go from very low volume to a significant amount of metastatic disease, so I think that makes a big difference. A two-year improvement is way beyond what we saw with both Prevail and 302 in the metastatic setting in terms of delaying metastasis. 

Dr. Alicia Morgans: That's true. Kind of thinking about, particularly this imaging component, which is becoming really an area of controversy I would say, and has been already in advanced prostate cancer. How does imaging play into this? I think you said that there were groups who participated in some of these trials that actually used PSMA, PSMA-PET for example, and there was a high potential screen-failure rate if that's what we were relying upon for entry criteria for these studies, but you could have a positive PSMA-PET as long as conventional imaging, I think, was negative. How do you think about that and does it mean something for that patient population?

Dr. Fred Saad: Well, the patients who did get a PSMA ... I mean, we're not supposed to really talk about those patients, it wasn't supposed to be nonconventional imaging, but many of those patients from personal communication were actually positive on PSMA, but negative on conventional, so they were eligible for the studies. That's the real world. I mean, if we start using widespread PSMA, we think that there's value in that, that population of M0 high-risk is probably going to be dwindling population. But at least in countries like Canada, and I assume in many countries around the world, we're far from being able to use PSMA on a routine basis. 

I think conventional is still going to be around for a long time and we're stuck with that reality. Unconventional imaging patients might not be metastatic, but we know that they're progressing quickly, they're at high-risk of becoming metastatic quickly, but even worse, they're at high-risk of dying. I mean, the PSA doubling time is one of the best predictors of actually dying of the disease, not just radiological appearance of metastasis. That's an important issue for patients and for physicians having to deal with these patients in that high-risk population.

Dr. Alicia Morgans: I agree and I think that it's encouraging to know that those patients, they were included in the all-comers analysis, those patients who were potentially positive on PSMA-PET, and still in an overall ... In overall MFS assessment, seemed to benefit from the treatment. Sort of wherever patients fall in that gray zone, I think it's encouraging that they may still benefit from the treatment. The other thing I wanted to kind of pick up on that you mentioned was this short PSA doubling time. 

I think, from my perspective at least, this data is really useful, particularly in those patients with the short PSA doubling time, because there are patients who have biochemical recurrence who have truly non-metastatic disease, or at least by the conventional imaging that I can get, and who may have a very slowly rising PSA over years potentially. How are those populations different, this kind of long PSA doubling time, versus a short PSA doubling time, and should we think about that when we apply the data from the M0 CRPC setting?

Dr. Fred Saad: I mean, that's critically important. What you're asking here is, do all patients with non-metastatic CRPC deserve to be treated? The answer is, absolutely not. I think that would be doing a disservice if we took this data that was in high-risk patients, patients with rapid PSA doubling times clearly at risk of becoming metastatic and even at risk of dying. But there are, on the other extreme, patients with slow rising PSA where their natural history is going to be so long that maybe intervening that early would actually be detrimental. This is the same story we had several years ago with just standard ADT in the biochemical failure in the hormone-sensitive study. 

We learned that we didn't need to treat every patient with a rising PSA. Those rising PSAs that are slowly rising are going to develop metastasis much later, are almost at negligible risk of dying of the disease, so we've learned to hold off on early ADT in low-risk patients. It's going to be the same thing with this scenario. High-risk need early treatment, because their risk of metastasis and death is significant. Others with low rising ... Others with a slow rising PSA probably are better watched and when the biology changes, then we intervene earlier, rather than later. 

Dr. Alicia Morgans: I think that's a great point and I'm glad that we agree on that point, because besides exposing those patients potentially to drugs for long periods of time, potentially even longer than the patients that we saw in the study, given the sort of slower progression and perhaps less aggressive biology of their disease, the side effects for that longer duration, also the cost of paying for these medications over that long duration of time, I think could be detrimental to all of us, which is not what we want to do. Switching gears a little bit, I wanted to ask you about one of the exploratory endpoints that we saw in the Apalutamide study, and would love to hear your thoughts on the second PFS, which frankly has a lot of people kind of scratching their head. What do you think about that endpoint?

Dr. Fred Saad: That was a very, in my mind-

Dr. Alicia Morgans: Can you define it for us?

Dr. Fred Saad: Yeah. In the SPARTAN trial with Apalutamide, we actually made the effort to not only capture the first MFS, but actually look at second PFS. That means patients who progressed, then went onto subsequent therapy, when did they progress subsequently? That's very important, because if patients when treated early in the placebo group, caught up in terms of efficacy. Then we could've said, "Well, there really might not be much difference between starting in the non-metastatic state, versus at first sign of metastasis." 

That's an important question to answer. But in reality, the curves continue to spread, so patients, even though they started very early as soon as they became metastatic, never were able to catch up to the patients who started in the non-metastatic state, telling me that over the long-term I'm very optimistic that the survival curves are going to continue to spread in favor of patients who started in the non-metastatic high-risk state.

Dr. Alicia Morgans: In the control arm then, these patients started on ADT. How long was it on average before they started on their first therapy, which was Abiraterone, right?

Dr. Fred Saad: Right. Patients who started on the placebo, who were just on ADT continuing standard of care, which is nothing else until appearance of metastasis, stayed in the non-metastatic state about 16 to 18 months. Within three months of becoming metastatic, they actually started treatment, which is much earlier than most of us would start treatment in mCRPC. These are very early interventions, and even though patients were treated very early, they were never able to catch up to the patients who started actually in the non-metastatic state. I think it tells me that, yes, in a predefined high-risk population of non-metastatic CRPC, starting early really does make a difference. 

Dr. Alicia Morgans: That's, I agree, a really important thing to learn. Not being able to catch up is something that we all fear and is something that we as clinicians, and certainly patients, want to avoid.

Dr. Fred Saad: Yeah.

Dr. Alicia Morgans: Something that's very important. We'll continue to think about this second PFS and-

Dr. Fred Saad: All right.

Dr. Alicia Morgans: Hopefully see it integrated into other studies.

Dr. Fred Saad: It was an important thing to do.

Dr. Alicia Morgans: Yes.

Dr. Fred Saad: Because if we are able to catch up by starting at the first sign of metastasis, we need to know that, because that means that probably prior to that it's not that important. I think now we have the data to support very early intervention, versus waiting till first sign of metastasis.

Dr. Alicia Morgans: I'm glad we ... You were involved in the study design, right? I'm glad-

Dr. Fred Saad: Well, we worked together on the steering committee, and so these were all important endpoints, and I have to congratulate Janssen for the work they did in the SPARTAN study, because they actually proactively offered therapy at first sign of metastasis. That's almost unheard of to actually volunteer active therapy at first sign of metastasis, because that's the best way in some sense to diminish any likelihood of seeing a difference in terms of overall survival.

Dr. Alicia Morgans: A risky study design, potentially.

Dr. Fred Saad: Absolutely.

Dr. Alicia Morgans: We also talked about other studies that didn't necessarily ... There wasn't necessarily this immediate action in terms of second therapy. What are your thoughts on that in terms of ... Was it in the ... The LATITUDE study, for example, there was a longer period of time if it wasn't so proactively offered?

Dr. Fred Saad: Right. LATITUDE in the hormone sensitive metastatic setting, patients were on ADT plus Abiraterone, versus ADT alone. In that scenario, patients actually became metastatic CRPC within about seven months in the control arm, because PSA started to rise. But it took longer before they had progression on imaging, and much longer before patients actually received therapy for mCRPC, and I think that's the real world. 

Dr. Alicia Morgans: True.

Dr. Fred Saad: We ended up with a much better survival in patients who started with a combination of ADT and Abiraterone upfront than leaving people do what is done in the real world, and we ended up with an almost 40% improvement in overall survival. Really, I think, not only is it important to start early, but it also avoids these delays that we see in the real world if we keep waiting and waiting for that second line of therapy that many of us delay for good reasons. We think patients should avoid toxicity, there's cost issues.

Dr. Alicia Morgans: True.

Dr. Fred Saad: But we forget that maybe there are benefits of starting early.

Dr. Alicia Morgans: Or we don't necessarily know, because this data is really just coming out, and I really appreciate you bringing it to light, and having us think about it. 

Dr. Fred Saad: Yeah.

Dr. Alicia Morgans: One of the things that I also thought was really special about this M0 CRPC data is that we see two drugs with similar mechanisms actually contributing similar data, so it seems that if we look at this kind of overall, it seems that targeting the AR, the androgen receptor in this setting, seems to be a really effective way to go, and we see that actually with two different agents. Would you agree?

Dr. Fred Saad: Absolutely. I mean, I think we had an era where, myself included, were very active in looking at preventing bone metastasis with bone specific targeting agents, and we were able to see positive effects with a drug like Denosumab, but it was bone specific. We weren't really targeting the cancer as a whole. With an AR target agent, we're targeting the cancer wherever it resides, and in the non-metastatic state, we don't really know where it is.

Dr. Alicia Morgans: True.

Dr. Fred Saad: But that class of agent has proven to be extremely effective in the post-chemo state, in the pre-chemo state, and now in the non-metastatic state. Really, it's a continuum that holds in terms of logic, in terms of metastasis for survival, in terms of symptomatic progression, in terms of PSA progression. Everything aligns in the right direction and I think just supports the fact that AR targeted therapy is probably the best way to go when we're talking about prostate cancer. 

Dr. Alicia Morgans: Great. What are your closing thoughts, your overarching message for viewers and listeners today regarding the data, the updates in M0 CRPC?

Dr. Fred Saad: Yeah. I think the way I look at this new data with non-metastatic CRPC, it just reinforces what myself and many others really believe, that a hormonal approach really is most effective early. I think we've pushed that to the maximum in the CRPC state. Now, the next wave of studies is, well, how do we optimally use this in the hormone-sensitive state, in patients that we know are destine to suffer from the disease, even die of the disease? 

We have to be able to identify those really high-risk patients and see what we need to do very early on to actually stop from saying, we can prolong life, but actually cure some of these very high-risk patients at first diagnosis. Will it be a combination of AR-targeted agents, in combination with chemo, in combination with the best local control, whether it be radiation or surgery? I think we are now at a state where hopefully we can cure very high-risk hormone-sensitive disease, to not even have to think about non-metastatic CRPC, because they won't reach that state.

Dr. Alicia Morgans: I love your optimism and I share it.

Dr. Fred Saad: Thanks. 

Dr. Alicia Morgans: I agree and appreciate in highly selected patients, for the right patient we can use these drugs, and we don't want to get to a point where it's too late, because we can't. We cannot make up the time that we've lost and that's a lot to learn from these studies. Thank you so much for your time and I hope you have a great meeting.

Dr. Fred Saad: It's always a pleasure.

Dr. Alicia Morgans: Thank you.
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