Urology Panel Jan 2014
Key:
LK - Dr Laurence Klotz
BT - Professor Betrand Tombal
WH - Professor Wolfgang Horninger
LK Hello and welcome to this round table discussion on the role of PSA as a marker in patients with metastatic prostate cancer. PSA has been an accepted biomarker for screening and monitoring of disease since the late ‘80s but over the last half decade this has been increasingly challenged particularly by the results of two recent trials, the ALSYMPCA and IMPACT trials. My name is Dr Laurence Klotz, I am Professor of Surgery at the University of Toronto in Canada and a Urologist at Sunnybrook Health Sciences Centre. I would like to introduce Professor Betrand Tombal.
BT Hello, I am Professor Betrand Tombal, I am the Head of the Urological Department in Clinique Universitaire, Saint Luc in Brussels, Belgium.
LK I will also introduce Professor Wolfgang Horninger.
WH My name is Wolfgang Horninger, I am the Director of the Department of Urology, Medical University, Innsbruck, Tyrol, Austria and also the Head of the European Prostate Centre of Innsbruck, Tyrol, Austria.
LK PSA has been used extensively both to diagnose and monitor prostate cancer since the late 80s but its role has been challenged over the last half decade by several studies, particularly in advanced prostate cancer. Two of these in particular are the ALSYMPCA trial and the IMPACT trial. Can you give us some background on these trials, the overall survival benefit and how this improves our understanding of the role of PSA in advance disease?
WH The IMPACT study and the ALSYMPCA study are both phase 3 trials, they have both as primary end point overall survival. In the IMPACT trial the agent called Sipuleucel-T which is an immunotherapy was compared with placebo and the study yielded a 4.1 month benefit in overall survival compared with placebo. In the other study, the ALSYMPCA study, new alpha emitter was compared with placebo also in patients with castration resistant prostate cancer, also this study showed a significant improvement in overall survival, it’s 3.1 months compared with placebo. What’s interesting in this study is that despite the fact that we see an increase in overall survival, we do not see very much movement in PSA, there is no decrease as we had expected that there should be, for instance in the IMPACT study there was just only 2.6% of the patients who had a PSA decrease of more than 50% and in the other study there was only 16% of patients who had a PSA decrease of more than 30%. This tells me or we have to be very, very careful with PSA in such therapies and also in such stages of prostate cancer. What I can see is that PSA is not a reliable progression marker in these stages of prostate cancer.
LK Professor Horninger, you raised a very important point. Professor Tombal, what is your view on this?
BT So indeed that’s a good question. PSA has been there for many years and one of the problems we have is that basically if you look at the literature supporting the use of PSA to predict the patient progression including that, I mean it’s actually very, very low. The problem is that PSA, it is something that is driven by the androgen receptor so basically it does represent one part of the tumour and how it grows and in contrast to many other cancers we haven’t used a lot of imaging technologies, we haven’t used a lot quality of life and symptomatic deterioration as a predictor of outcome and we have educated our patient with the PSA and that’s normal to some extent before because these guys were diagnosed with PSA, the first time they had hormone therapy usually was because PSA was increasing so these patients are PSA driven. Now we realise that the way we define progression and not only PSA progression but also image progression is maybe not fully related to the impact of the disease on the patient itself and we have two, I would say, wonderful examples. The first one is using bone targeted therapy and most especially Radium-223 in the ALSYMPCA trial and the other one being using immunotherapy with PROVENGE in the registration trial. When you look at these, they have very little impact on the PSA, meaning what? They have very little impact on the part of the tumour that is producing PSA but they both share in common that they are working more on the host, on the patient themselves than on the tumour. If you think about bone targeted therapy, what they do is they make the bone more resistant, they help the bone to heal to the aggression of the cancer and because of that you can live longer with a higher burden of cancer and this is probably the way immune therapy work as well. It doesn’t necessarily kill the tumour. It makes the patient more resistant and it makes them live longer with a higher burden of cancer. That is a really important message, The message is that it is not only the way that PSA tumour component grows that’s going to make the prognosis of the patient but also it does react to that amount of cancer and if you can’t help him react better to that amount of tumour, he’s going to live longer and at the same time it stresses also to look at how we can see how the patient is living with the cancer and more than ever component like how the patient feel pain, fatigue and other side effects are so important to make a really good understanding on where is the patient going and how much is being, I would say, attacked by the disease.
LK We saw significant PSA declines in the enzalutamide and abiraterone trials and yet no effect on PSA is the ALSYMPCA and IMPACT trials. How is this possible?
BT So once again I see your question is because probably you also are PSA driven and basically these are two families of targeted therapies, three family if you include drugs like Sip-T (Provenge). I mean the target of enzalutamide is they are a component of the tumour and because PSA is an AR dependent protein, you are basically targeting the PSA component so it is obvious that PSA will decrease. If it wasn’t the case it would simply mean that enzalutamide is not hitting the target. When you refer to a drug like Radium-223, PSA producing cells is not the target. The target is the bone micro environment and actually you can use with Radium-223 you can use all the biomarkers such as alkaline phosphatase that may drop significantly but basically it’s the same, it’s always what I like to call the ying and the yang of the cancer. On one side you have the tumour and you can hit the tumour very well with a specific agent like enzalutamide and on the other way you’ve got the host, the microenvironment where the tumour is growing and if you hit that equally strongly, you’re going to have the same benefit and that’s why I’m so enthusiastic because clearly the future, what we haven’t done yet very well is to hit at the same time the tumour and the microenvironment and then hopefully get some synergistic effect then even have patient living longer. The problem is that as long as we consider that PSA is an overall marker of response, we’re going to have trouble understanding the benefit to the patient. It is then now to realise that PSA is not a prostate cancer marker, it is an AR marker so if the patient has an AR sensitive component, this will be hit by enzalutamide probably at the beginning very hard. If he has other important component we may not see any PSA rise or drop but it doesn’t mean anything, it doesn’t mean that the tumour or the patient haven’t been hit successfully.
LK Thank you very much. The newer generation of agents, for example Radium-223 and Prostvac which showed us six month survival benefit in the phase 2 trials both seem to have their action despite not influencing PSA. How does the mechanism of action of these two drugs enable them to be effective independent of PSA?
WH Also this is a very good question and again I have no scientific proof to answer to this question. I think nobody knows that it was not evaluated why these two medications work this way so that there is no decrease in PSA. What I can say in general is in these tumor stages and for these therapies we do for these patients, do not rely on PSA only, we have to do radiographic examinations such like CT or MRI or you can do bone scans or better PET scans.
LK Professor Tombal, what is your view on this?
BT So I would not use the word newer or older, I would really say a different class of agent because this is really what’s important is different class of agent. I like to take an analogy, I mean if you’re a man and they say okay, you have to climb a mountain, that’s a good analogy because we know that usually when you’ve got that point of the cancer, you know unfortunately these guys are starting the last rise, okay and living with cancer is like carrying a big bag and as long as you climb, the bag is getting bigger and bigger and bigger and you’re getting weaker, weaker, weaker and at some point you fall because the bag is too heavy and you can’t or you’re too weak. The traditional view of oncology, we had using hormonal agents or chemotherapy was to make the bag smaller but sometimes we would make the bag smaller but even the patient weaker, think at aggressive chemotherapy for instance. Now there is a totally different view is that we won’t necessarily make the bag smaller but we’re going to make the patient stronger and in the case of prostate cancer, clearly you get weaker because your skeleton is destroyed and by making the bone microenvironment stronger, the patient can start climbing again, not because the bag is smaller but because the guy, you, is getting stronger and we had seen that a little bit with agent like pure simple bone remodelling agent such as zolendronic acid and denosumab where we could improve quality of life and there was some indication with zoledronic acid that we could eventually increase a little bit overall survival, know that we have much stronger bone targeting agent. We can see that clearly by making the skeleton stronger by making the patient stronger, he will walk higher.
LK Therefore is PSA still useful to quantify disease or as a marker of disease in patients who are being treated with these newer agents?
BT Your question is complex. A very famous urologist once told me that the evidence would be that we should never use PSA, you know my mother she had colon cancer a few years ago. She goes to the medical oncologist every six months, she has got a CT, a bone scan and he say okay, everything is fine. With PSA what we have done is anticipating the diagnosing of a certain part of the disease and we’re doing a lot of anxiety so if you ask me my opinion, during CRPC I would like to teach my patient not to rely at all to PSA to the point I wouldn’t do it, okay? It may seem extreme but we could speak hours about that idea. Now it won’t happen because like I mentioned, these patients are PSA educated. Where we have to work a lot is really to make clear that PSA alone will never be enough any more. You need more than PSA. You need PSA. You need imaging and you need more importantly clinics and it’s the combination. A patient receiving a drug which after six weeks is doing better as an improved quality of life and a diminished pain is feeling better, I don’t want even to look at the PSA. PSA should come last and we have to change that and it’s going to take a lot of education with our patient.
LK Professor Horninger.
WH I don’t think that PSA is an appropriate marker in this stage of the disease and also not for these therapies. I think what we should add is if you want to know what’s really going on in this disease and the body of the patient is that we have to do CT scans, MRIs, we have to do for instance bone scans or better PET scans.
LK What about patients with early stage prostate cancer or those being treated with abiraterone or enzalutamide. Does the PSA still have a role in such patients?
BT The good question we have is whether based on a PSA assessment after six months, if the PSA doesn’t decrease or slightly increase, does it mean there is no benefit of the drug. When we use an agent like Sip-T or Radium-223 that is clear, you can consider that the benefit is somewhere else. If you take an agent like enzalutamide or abiraterone that specifically target the AR and after six, nine weeks, six months you have no change in PSA, it is hard to say is it a failure and I would say that I would be inclined to change the treatment and to switch to something else but once again we don’t have good scientific evidence to this question and once again it start to the point, and to me the most important point, should we initiate treatment based on PSA rise only? When I talk to my patient I always try to convince them not to. I always like to rely on something more, imaging, clinical deterioration. So to me, because of PSA and because of drug who have a major affect on PSA, what we might do actually is expose more and more patients to early treatment with hormones and probably not necessarily increase the overall survival a lot but increase the exposure to drugs a lot so that we’re going to increase toxicity and most importantly we’re going to increase cost, so these studies have been done and awaiting this study, I think that it is our duty to not rely on PSA alone but incorporate different element in the decision to treat.
LK Professor Horninger, can you please elaborate on that?
WH PSA in early stage prostate cancer is a good marker, it’s not an excellent marker but it’s the best marker we have and PSA after definitive therapy, for instance, after radical prostatectomy is an excellent marker which was the first approval in 1986 by the FDA that PSA can be used as follow-up after radical prostatectomy.
LK If the PSA increases significantly while the patient is being treated with the newer generation agents, does this necessarily indicate disease progression?
WH Well it must not but it unfortunately often is. What we have to consider and what we have to think in these patients is not to focus on PSA alone. Again I have to say if we really want to check what’s going on in this disease, don’t rely on PSA alone, make radiographic examinations, CD scans, bone scans, PET scans or MRIs.
LK Professor Tombal, what is your view on this?
BT When a patient is monitored closely and you see a really abrupt rise in PSA, very often it means a rapid progression of the disease so that’s easy because usually it’s not necessarily isolated, it’s a matter of timing. If you repeat an imaging or you look at the patient a few weeks after, usually it means I would say cancer failure in general. The question, the clinical question about defining progression or not comes more from patient with a slow increase in PSA because you have many patients with a slow increase in PSA and no progression from the clinical or from the radiological side. These are the difficult to manage. The guy that you’re following and his PSA is doubling in six weeks, it is very seldom that you won’t have clinical deterioration rapidly after so I wouldn’t make these patients necessarily a very difficult case. No the difficult one is the slow rise with no change in imaging and clinics because it generates a lot of anxiety from the patient and from the patient a sudden realisation that probably the treatment I have is not active any more which is far from being true but the patient at that point will start questioning the treatment and the whole strategy. These are the difficult patients.
LK Thank you very much. Conversely in patients who are being treated with Radium-223 or other next generation agents in whom the PSA is failing to respond, does this mean that the drug is ineffective or that it is working through a PSA independent mechanism?
BT I think if you ask me Radium-223 and Sip-T, these are good treatments but you better do the education before you start the treatment because do not forget that it’s a new treatment so patient will come, all the treatment they had so far was immediately followed by a drop of PSA. If you weigh that they have received one or two injections hoping that they’re going to be the patient with a drop in PSA and they aren’t, then you’re going to be in problem so this is why these drugs, which are based on new mechanism, they require at least a minimal patient education. Before you start this drug, you have to start sometime with the patient, explaining to them what you expect from that treatment, how are you going to monitor that treatment and please, from the beginning to say that we won’t necessarily make the tumour smaller, we’re going to make you stronger so don’t expect too much of a PSA change. If you’ve got it, that’s a bonus but if you don’t have it, it does not mean at all that the treatment is not working and we got other indicators like pain because usually it’s going to be given to patients who experience pain, alkaline phosphatase but please explain from the beginning or you’re going to be in trouble after one or two injections and you’re going to make the decision to change the treatment on a false assumption that it’s not working.
LK Professor Horninger.
WH Well as you know, we are all PSA driven. All the doctors, all the urologists, oncologists and also almost all the patients are PSA driven. If the PSA goes up that’s also in my opinion not a very good signal but it must not be a very bad sign. Again in these stages of the disease you have not, or you have to do other examinations other than PSA, do PET scan, do MRI, CTs or bone scans.
LK In both the ALSYMPCA and the Prostavac VF phase 2 trials, the drugs were effective and improved survival, despite the fact that there was no effect on PSA. What does this tell us about the role of PSA as a biomarker for response in patients with advance disease?
BT To me, the most important message of this trial is that we have not reached the tipping point that we should not regard only PSA. I’ve got nothing against PSA but PSA alone is not only. PSA is a marker of one part of the tumour, the AR dependent. We need marker to look at the AR independent component and that could be imaging. We have cases of patients with a few metastases, unbelievable PSA drop and when you repeat the MRI after six months, you’ve got four metastases who have popped up simply because they don’t produce PSA and the third one and even more important than the tumour component itself is the patient component. How can we assess not the effect of a drug on a cancer but the effect of the drug on the cancer on the patient so what has the treatment done to the overall patient itself and that’s really the challenge. The problem is that with this new agent, we need to find the new way to assess the patient and that’s a challenge that is, I believe even bigger than the clinical trial development itself.
LK Do you concur with this Professor Horninger?
WH Well these two studies, the ALSYMPCA study and the IMPACT study clearly showed us that PSA is not appropriate in this stage of the disease and it’s not appropriate for these therapies. Again I have to say, don’t rely on PSA only. I know PSA will always be with prostate cancer treatment. You will always have the PSA and the patients and also doctors are focused on PSA but it’s better to do radiographic examinations than to rely on PSA alone.
LK What are your thoughts about the incorporation of new biomarkers or bone scans or other imaging modalities to quantify extensive disease in patients with prostate cancer and bone metastasis?
WH There are some biomarkers but these biomarkers, they have shown that they can enhance the ability of PSA in the early detection of prostate cancer, it’s for instance pro PSA or it’s prostate health index or it’s the PCA3 but to my knowledge, all these markers, they are not tested in advanced prostate cancer. We do not know if they work here and again what we can do, it’s the only thing what we have, is to radiographic examinations, to CTs, bone scans and then you should know what really is going on with the disease of the patient.
LK Professor Tombal, what is your view on this?
BT I think clearly in the next ten year we’re going to see the emergence of imaging and just think about localised prostate cancer. PSA more and more is completed with MRI, it is very seldom that we would do a repeat biopsy or we would do a radical prostectomy without having an MRI so clearly this will come for advanced prostate cancer and to me it is especially more important that we’re using new hormonal agents where they’re going to have a major effect on the PSA so it’s going to be like a ceiling effect and you won’t see what is going outside the PSA environment so to me now it is clear that you need to embark new imaging technology where there is going to be MRI or PET choline or PET FDG or whatever, we need to embark this and we need to embark them to start with in the clinical trial to validate their use and beside that I’m sure we’re going to have new biomarkers. We already have CTCs but I don’t know, it relies to a drug like Radium or vaccine therapy but clearly we won’t rely on PSA any more and I think also we’re going to learn to incorporate all the biomarkers, think about pain, it’s a simple biomarker and think about how many of us use proper pain scale on an everyday basis so clearly I wouldn’t say it’s the end of PSA, it’s still going to be there but it’s the end of PSA alone deciding to treat and follow a patient, that I’m so sure.
LK Men have become used to relying on PSA as a marker for the extent of disease and response to treatment. What kind of conversation should the urologist or oncologist have with the patient regarding their interpretation of the PSA with these new agents?
BT I like that question. Actually a friend which is a neuropsychologist told me a few years ago because he had some PSA problem himself, he told me something very interesting. Think about PSA as an addiction and when you speak about PSA, try to think how you would speak to one of your patients about smoking or drinking, okay? It’s not that it helps them. They need it. I mean they need it. We know that in a clinical trial where we try to blind the PSA, they go, you know, at the lab on the corner to get their PSA so really you should not under-estimate that and just to tell somebody your PSA is useless, that won’t go. We have made them addicted to PSA, we need to de-intoxicate them from PSA and usually I try to start that very early, by the time they’re getting castration resistant under hormone therapy and I say listen now, your PSA doesn’t mean a lot of thing any more, we’re going to need to add something on top of PSA and what that PSA will do is help us decide when we should have something in terms of imaging and diagnostic. I don’t say it works but at least if you start thinking about PSA as an addiction and you try to get that comprehension, it helps you maybe finding better words for your patient. Just to say your PSA is not decreasing, that’s nothing, it won’t work, it won’t work, you need to have a long talk and it takes time.
LK Professor Horninger?
WH Well we are all PSA driven. We doctors are PSA driven, almost all patients are PSA driven. What we can do is on a basis of confidence make an honest talk with your patients and tell them what we know about PSA and what we do not know about PSA in these advanced stages of prostate cancer. I think we have to tell them that PSA in these advanced stages is not as important as for instance after a radical prostatectomy where PSA is a perfect marker for disease progression. That’s what we have to tell the patients.
LK So when making a decision as to the role of PSA and guiding treatment, have both the extensive disease and the type of treatment become important considerations?
WH Yes of course it’s important to know what stage of disease the patient have, it’s absolutely important to take that into consideration if you do, for instance, therapy against bone mets that it must not be dissuaded the PSA will drop. You just have to look at your results you have and then you have to make the right interpretations and then you have to talk to the patients, tell him what’s going on in his body, tell him what’s going on with his cancer and then discuss with him what to do next.
LK Can you please elaborate on that Professor Tombal?
BT That’s a difficult question because actually it’s not necessarily in deciding when to start the treatment. I think PSA has grown as a concern in the decision when to stop a treatment. Think for two minutes, I mean in the modern environment you will start a treatment because the patient has PSA progression, imaging progression or clinical progression. In most of the cases it will be PSA progression and then the patient will take a lot of hope in that new treatment and the problem is that the first thing he will look at will be PSA so clearly the challenge is not PSA as a decision to treat but PSA as a decision to stop or switch treatment and that’s what I say, I say okay it’s useful to decide when to start but we will never decide when to stop basing on PSA.
LK Professor Horninger, Professor Tombal, thank you for sharing your thoughts with us today, it’s been a great pleasure.
WH Thank you very much for inviting me. Thank you.
BT Thank you, it was a pleasure to be here today with both of you.
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