Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial - Fred Saad


Alicia Morgans and Fred Saad dialogue about the details of this phase 3 trial by the Quebec Cooperative Group of Radiation Oncologists in patients with high-risk localized prostate cancer. The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 months of ADT.

Biographies:

Fred Saad, MD FRCS Professor and Chief of Urologic Oncology, University of Montreal Hospital Centre, CRCHUM

Alicia Morgans, MD, MPH


Read the Full Video Transcript:

Dr. Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist at Northwestern University, and I am very pleased to have with me today, Dr. Fred Saad, who is Professor and Chairman of Urology at the University of Montreal Hospital, also the Director of the GU group there, and we asked Dr. Saad to come in with us today about a recently reported phase three trial by the Quebec Cooperative Group of Radiation Oncologists. Thanks so much for coming to talk with us today, Fred.

Dr. Fred Saad: My pleasure to be here.

Dr. Alicia Morgans: So, can you tell us a little bit about this study? It was a phase three study looking at men with high risk localized prostate cancer and was really trying to understand how long we should be using androgen deprivation therapy in this setting. Really trying to define what that optimal duration would be.

Dr. Fred Saad: Yeah, exactly. I think we all recognize that we have to give credit to the EORTC  led by Bolla who first reported that radiation therapy alone in high risk, locally advanced prostate cancer was clearly insufficient and then by adding 3 years of androgen deprivation therapy you clearly improve disease free survival, cancer specific survival and even overall survival. Then they followed up with a study of 36 versus 6 months, which clearly showed that 6 months is insufficient in those patients. 

The question on many people’s minds including the cooperative group here in Quebec of several large radiation therapy centers, was do we really need 36 months in these high-risk patients, because we all recognize the side effects of ADT. The study actually did what people actually do in the real world, was trying to cut down on 36 months without that much evidence. So they compared 36 months versus 18 months ADT in this high risk locally advanced population. They included over 600 patients, 630 patients that were randomized to radiation plus or minus 36 or 18 months of ADT.

Dr. Alicia Morgans: I commend the team for being able to enroll such a large study and really helping to identify a question that needs to be answered because as you mentioned patients want to have enough, but they don't want to have more than they need in terms of hormonal therapy. Will you tell us a bit about the findings, to me it's very encouraging and looks intriguing actually, so can you tell us a bit about the findings?

Dr. Fred Saad: Yes, so this group in Quebec is pretty homogeneous. The same kind of machines, the same kind of attitudes so within a little less than 8 years they randomized all the patients, so I think a short enough amount of time that there wasn't much change in how radiation was delivered. Now they have almost 10 years of median follow up and what they actually showed was - this was supposed to be superiority randomized trial, so we can't talk about whether it's superior or non-inferior, but the results so far is that there really is no difference in terms of overall survival, no difference in cancer specific survival. Whether you had 18 or 36 months of ADT, which is extremely reassuring for us as clinicians, but also for patients that 18 months looks like it might be enough for these high-risk patients.

I just want to come back to one minor thing. The definition of high risk disease. Although it’s still the same, when we look at the kind of patients coming in now, their high risk is PSA's of above 20 or Gleason above a 7, Gleason 8 to 10 disease or T3 or T4, and that's or. Clearly a patient who has a PSA of 21 who's Gleason is 6 or 7 is not the same as a patient whose Gleason is 9 T3 with PSA of 50, even though they would all be eligible. So clearly 36 months might not be required for most patients that are coming in with one of the three high risk features, so this was very reassuring as a result. I guess some of the other results is yes, you do have more biochemical recurrence if you’re giving all the 18 months, but that comes back to the intermittent ADT, which I think is quite acceptable for nonmetastatic patients. You can expect that if you get 18 months, you might have a higher risk of requiring to go back on ADT, but that's okay. Those that don't need it were avoided 18 extra months of ADT.

Dr. Alicia Morgans: I absolutely agree. I think what's important here is the nearly 10 years of median follow-up 9.4 years. One would expect, looking at it from a clinician standpoint, or even from a patient point of view I would think that if you can't demonstrate superiority of essentially 36 months over 18 months by 10 years, than probably it's not going to be better. I appreciate that you mentioned it's not a non-superiority design that probably would have boosted the patients' numbers and would be a bit more complex or different in terms of the analysis, but clearly, we're not showing superiority. At this very lengthy follow-up I think that's really important. 

I appreciate too your explanation in terms of why we might be seeing this and that's probably because even in patients defined as being high risk, this is a heterogeneous population and we have to use our understanding of all of these risk factors together. If you have only one of these risk factors it makes it at least from my perspective great sense to potentially consider 18 months for those patients based on this data. If you had a patient with very high risk, localized disease, who may have constellation of three of these high-risk features, would you change your management, Fred? Would you say despite the data maybe I will give them 36 months? How would that effect you?

Dr. Fred Saad: Yeah and that's something we all do in the clinic, right? We have a  feeling that this is a really high-risk patient and whatever I'm going do is going to recur. So in those kinds of situations and I'd like to hear what you would say, but I think even 3 years might not be enough and we might have to add chemotherapy or some of the new generation hormonal cause those patients regardless of what we do are destined to fail. So obviously we will in the patient that has the three high risk features combined, consider 3 years maybe even consider putting them in a clinical trial where we add something even more than ADT alone as adjuvant to radiation. I think that's what we're starting to refine our definitions I think D’Amico did a great job to simplifying low, intermediate, and high risk, but we know that within all of these groups there are subgroups and I think we have to be attentive as clinicians to the subtleties of who we're treating. 

The only cause in truly high risk patients that I would go less than 3 years is if there really is issues of quality of life. We might cut down on the 3 years if the person has a PSA that goes down to undetectable, has real issues in tolerating the ADT, but otherwise I do continue to think 3 years is our gold standard for truly high risk, locally advanced disease.  You know, PSA of 100 in a patient with Gleason 8 disease with a T4 disease, I mean we're all very uncomfortable when we see that kind of patient, especially if they're young coming into the clinic. 

Dr. Alicia Morgans: Absolutely, I think one of the most exciting things that we're doing is trying to think more of how do we identify those patients, so there is a lot of exciting protocols in place to try to understand maybe from a molecular re-stratification standpoint who these patients might be and also to use additional therapy's in addition to ADT. I agree with you, I think that ADT alone, yes, is very useful in combining that with radiation in these high-risk patients and  we see we're prolonging survival, but if patients are recurring, even if it's a biochemical recurrence, we're clearly not curing them and ultimately that's what we're trying to do by combining hormonal therapy with radiation. Not just delay the time for their testosterone recovery and then allow their disease to grow back.

I agree with you and I look forward to, I know there was chemotherapy data of the ROTG 0521 data that suggested that if we use chemotherapy sort of on STAMPEDE or CHAARTED recipe of six cycles for high risk patients in a post RT setting, we might be able to further eradicate the disease. I do look forward to seeing some of that data, but I also appreciate that you as and your team, and the team that did this work think about quality of life as they try to make these decisions and these judgment calls because until that chemotherapy data I don’t think has come out in a paper data yet, just in an abstract, and this data though I think really does suggest that we do change quality of life. We can affect the quality of life with the treatments that we give in a setting of radiation. Can you go through, it was lovely in this paper that they were so thorough to report their quality of life data, can you go through those findings for us?

Dr. Fred Saad: Sure, so in terms of quality of life, from the very beginning this was an important aspect for these investigators because they were actually willing to accept maybe slight inferiority in terms of the outcome if the counterpart would be improving quality of life. It's really quite striking just to what extent and it was very statistically significantly better the quality of life with only 18 months compared to 36. So the fact that we're not losing any disease-specific survival or overall survival by giving 18 months and clearly improving quality of life compared to 36 months, I think makes this something to really consider as a new standard. 

Clearly patients want to live longer but not at all costs. We all know if you give someone 3 years of ADT, especially if they're older, they might never recover their testosterone.  I think one of the reasons quality of life was clearly better is that when you give 18 months there is a much higher likelihood you will recover your testosterone levels, regain your capacity for activities, the fatigue that comes with ADT, and that's obviously putting aside all the other issues in terms of bone loss and all the rest and the sexual side effects that come with long term ADT. So clearly I think that this is a big advantage and a new reality. With everything, we're doing in clinical trials, quality of life is a center piece of the research because we're not doing tremendous in terms of improving survival so we really need to concentrate on quality of life like in this analysis.

Dr. Alicia Morgans: I could not agree more with you and I think it's interesting that overtime patients even seem to be feeling more comfortable in voicing that as a main concern. Patients have always said, “ I want to make sure I can live as long as I can live”, and they will often talk about quality of life but it’s almost as if it's an afterthought, but I've had more and more patients come in and say, “I really want to understand what this is going to do to me and how I'm going to feel and what my life is going to look like, I don't just want to live longer”, and I'm glad as a community of researchers we're listening to that from our patients, and of course we agree with them and we want to contain quality of life as we extend life.

Dr. Fred Saad: When we're talking about prostate cancer we're not talking about 30 or 40 year olds. Where they'll have time to recover and take advantage of another 30 years. We're talking about patients that are often in their 60s, 70s, and sometimes even 80s where clearly affecting their quality of life, has an impact sometimes for all the time they have left to live. So I think we have to be very conscious of what we do to patients and not be overly obsessed of what we call PSA and think much more in terms of the overall management of a disease like prostate cancer.

Dr. Alicia Morgans: Absolutely, so Fred what would you say your take home message from this paper is. It sounds like from your perspective this is practice changing, what would you say?

Dr. Fred Saad: Yeah, I think it's clearly a practice-changing study that many of us when we said to a patient that there was high risk that they were going to take 3 years of ADT felt extremely uncomfortable if patients were complaining of quality of life issues in stopping before 36 months. I think that if this doesn't become a new standard, at least it becomes some way of reassuring physicians and patients that it's okay after 18 months to maybe take a break. Knowing that there's a chance that we might have to come back to ADT, but if we can take a break for 3, 4, 5 years, I think that's very welcome for patients. I think that for me it is practice changing because we're going to reflect on, I don't think that it's new standard, but it's practice changing in the sense that it's something that can be considered and like we both said, I think we need to refine but what we mean by high risk and maybe modulate.

The low side of high risk, I think that 18 months should be highly considered, and the paper actually showed the patients most likely to get a benefit from the 36 months were the Gleason 8 to 10s, which we all know is probably the driving factor for patients and not getting long term control of their disease. I think this just helps us maybe personalize how we treat our patients with high risk disease.

Dr. Alicia Morgans: Absolutely. So thank you so much for reviewing the study with us and for contributing. I'm sure you contributed brain power and patient power to this study and I really appreciate your expertise and your time. Thanks so much.

Dr. Fred Saad: Thanks so much for the interest in this. I think it was a great discussion and appreciated it.