Evolving patient management in metastatic and non-metastatic castration-resistant prostate cancer

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Published: 12 Nov 2012
Views: 6970
Professor Noel Clarke, Dr Heather Payne, Prof Karim Fizazi,Prof John Fitzpatrick, Prof Bertrand Tombal

Professor Noel Clarke - Honorary Professor in Urological Cancer/Consultant Urologist, Manchester University, talks to ecancer TV with Dr Heather Payne - University College Hospital, London, Prof Karim Fizazi - Institut Gustave Roussy, France, Prof John Fitzpatrick - School of Medicine & Medical Science Mater Misericordiae University Hospital & University College Dublin, Ireland and Prof Bertrand Tombal - Saint-Luc Hospital, Catholic University of Leuven, Belgium, about recent advances in the management of patients with prostate cancer.


The panel discusses who to treat and who not to treat, with emphasis on first-line therapy. Experts highlight recent data which suggest that the duration of hormonal therapy is an indicator for the response to second-line therapy. Results from the 301 study and the relationship between performance status and ECOG status are also discussed with a focus on individualised treatment. Experts debate strategies to determine patient responses, and highlight the need for trials investigating the value of biopsies and biomarkers with a focus on heterogeneity of tumour cells. 


The experts discuss whether anti-androgen therapy should be used upfront or after cytotoxic treatment and agree that further trials are still required examining cross resistance. ‘Combination’ treatment rather than sequence of drugs is also highlighted as an important option.


Skeletal integrity is discussed, with the emphasis on the need for supportive care for bone. Bisphosphonates and denosumab are discussed, together with the results of last year’s study with alpharadin which suggested a direct anti-cancer effect. Overall, there is a need to develop drugs which can prevent cancer cells from binding to the bone to improve patient outcomes.


This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

NC: I’d like to welcome you to the prostate cancer debate for 2012 in Paris. We’re going to discuss aspects of treatment relating to metastatic and non-metastatic castrate-resistant prostate cancer and this is a field in which there have been considerable advances, many exciting advances, in recent years with major publications throughout 2011, 2012 and further to follow. With me to discuss aspects of this is a panel of distinguished cancer specialists, some urologists, some medical oncologists, some clinical oncologists, and we’re going to go through some of the issues relating to patient presentation, treatment, disease doses, combinations and so on. I hope this will help shed some light on some of the clinical questions which I’m sure you will have in your clinics with patients on a week by week basis. I’d like to start with a question of who to treat and who not to treat and with what agents, if I could perhaps come to you first, Karim. When a patient comes in with castrate-resistant prostate cancer or a patient you’ve previously been treating starts to develop signs of castrate resistance, what’s your preferred option as the first line of therapy and how do you make that decision?


KF: I’m not sure I can give you only one answer to this question because I really believe that you need to personalise therapy, hopefully in the future based on biomarkers, but even now based on some clinical parameters. Obviously you need to take into consideration patient age, other comorbidities which may or may not be in favour of some given drugs, but you also should probably take into consideration what you know directly or indirectly from the biology of the disease. For example, a patient who progressed rapidly while on androgen deprivation therapy, in my experience, is quite unlikely to benefit from a second line hormonal therapy, whatever that is. Then you may, for such a gentleman, consider either chemotherapy or another non-hormonal therapy agent. Now, in a patient who had a very long previous duration on ADT, androgen deprivation therapy and who progresses first is very likely to benefit from a second line hormonal therapy. At the moment, with the drugs we currently have, there is no demonstration for PFS improvement and overall survival improvement with either cetoconazol, DS, steroids, AR inhibitors, but these are the drugs we’ve been traditionally using in this particular setting. Now we have more data coming with abiraterone suggesting with the 302 trial that abiraterone can only postpone progression, not only PSA progression but also clinical progression, radiographic progression and likely overall survival.

NC: Thank you. Bertrand, can I just come to you to tease out this issue of whether a second line hormone therapy should be used if there has been a relatively short duration of response. We have a good knowledge that the newer agents coming through have got different modalities of action.


BT: What we know is that we have data, first, these new agents actually are better agents, mimicking the action of older agents we have been using as urologists for many years. We know already that the duration of hormone therapy, if you look at maximum androgen blockade, second line hormonal manipulation, is clearly one of the most important indicators of the chance of responding to a second line. There is a very famous study by Oliver Sartor clearly showing that for patients who had a response time of less than nine months, adding any additional hormone therapy, and I would even say whatever the mode of action is, is very likely to give additional response. So I would like to add on on what Karim says, that today amongst the factors we have, the duration of the response to hormone therapy is probably the most important indicator in the first line discussion, chemo versus second line hormonal manipulation.

NC: Thank you. John, as a practising urologist, you know very well that a number of the patients who are coming into your clinics or are sitting on your urology wards are actually of poor performance status. How do you square this circle in that you might have a patient with metastatic disease whose disease is progressing who you think might respond and yet might benefit from chemotherapy? How do you go about instituting that in your hospitals?


JF: The whole question is relating to things like performance status, as you said, but all of these drugs are introduced for metastatic castrate-resistant prostate cancer and metastases are generally to bone and bone metastases cause pain. So pain is a vital issue here. I think, in relation to your question specifically, even if their performance status is poor, the balance between the symptom deterioration and the ECOG status is something that has to be considered very actively. Now, as I said, we discuss all of these issues at the multidisciplinary team meeting so, in other words, somebody isn’t just going to suddenly be transferred from the urologist to the medical oncologist just like that, there’s a big discussion about it, hence the importance for urologists to know about these drugs and to know about the mechanism of disease. That’s my summary, of perhaps what you’ve been asking.

NC: That’s a very clear summary, thank you. Teasing that issue a little further, I’d like to come to you, Heather. In the 301 study post-docetaxel, the information from the sub-analysis suggested that the poor performance patients didn’t do as well with treatment. Do you sub-stratify those patients to work out who is going to get a good response or do you just give it to everybody and assess their response?


HP: Again it’s an individualised response and those patients with performance status do sadly often have more limited options because that may be due to their cancer progression or may be due to comorbidities. So I think there are a group of patients with a poor performance status who I’ve seen have very good responses to abiraterone.

NC: Which brings me into the next issue which is a quite thorny one for many clinicians and that is how do we assess response? Do we use conventional biochemical measurements like PSA, do we use symptoms? How do we do it? Bertrand? 

BT: I think first it will depend on what stage of the disease you are. If you are indeed in a patient who has pain and deterioration of quality of life, I must say I’m already very happy if the patient improves at that point. If we are in a setting of asymptomatic patient, that is getting more tricky because clearly what we know at least is that we can’t just take a decision on one marker. We have to sort out what I call the discrepant patient, meaning those that have a huge PSA response and a mild progression on bone scan. Once again it will be individualised but I think that what has to drive the decision in the end is how the patient feels. I think that we knew drugs in the past like satraplatin, which Karim will remember, that was a chemotherapy that was working very, very well and the patients were feeling much better but we had to stop because they were progressing, So I think what should drive is first how the patient feels – pain, quality of life, and then I would say a mixture of biochemical and radiological progression.


NC: And that’s very important, isn’t it? Karim, a number of these patients will get pain and we know that that pain may not necessarily be related to the progression of their cancer, it might be a supplementary effect, for example, a collapsed fracture of a vertebra which looks like a metastasis but actually isn’t. Do you have any scheme for investigating these patients throughout the course of treatment?

KF: I have still to say that most patients suffering from pain are actually suffering from pain related to their cancer so this is still very true unfortunately. But you’re right, these patients can be quite old, can be for a long time on ADT and can actually have osteoporotic fractures so if a patient quite brutally suffers from pain, specifically if it’s a pain in the back and it’s very near located to a vertebra then we tend to image systematically this patient, at the very least with an X-ray and more and more with MRI. One thing is only to separate osteoporotic fracture versus pain that is related to bone metastasis but another one is also to make sure that we detect spinal cord compression before it actually happens clinically. So we do more and more MRIs.


NC: And looking further ahead, do you think that there’s anything more sophisticated in terms of either imaging or biochemistry or cancer genomics which might help us to isolate those patients who might benefit one way and another from early intervention, specific sorts of treatments and so on?

KF: That’s really the question of personalised medicine for prostate cancer patients and metastasis. Unfortunately we are far behind compared to our colleagues doing breast cancer, colorectal cancer, lung cancer and others. One obvious limitation in prostate cancer is really to get some tissue because either you consider making a study, a molecular study, on the prostatectomy specimen of a biopsy but it can be ten years before so it doesn’t necessarily reflect the on-going disease when you’re treating patients with metastatic disease. Or you try to do a biopsy of metastasis deposits which means a bone biopsy in most cases, which also has a challenge because it’s not technically easy to do, it can be painful, and analysing the tissue can be very challenging in the lab. So this is really what we’re trying to do; we’re also trying to do some lymph node biopsies and liver biopsies and consider ERG expression, AR, also probably p10, MEK expressions or abnormalities. We will try to collect these samples in a series of patients with early metastatic CRPC and the goal is really to try in the future to better identify which patients should benefit from which drug based on all the molecular assessments of their tissue.


NC: And circulating cells, where are we up to with that?

KF: We are actually doing CTC assessments in parallel to that. The nice thing with CTCs is that this is easy to do from the patient’s perspective, it’s just a blood test so it’s not painful. The bad thing is that, one, it’s expensive and, second, most data comes to enumeration, it’s generally counting the cells. What we know for now is that the higher the cell number, the worse the outcome. Having said that, can you really integrate this data in your current practice? Probably not. It’s not because a patient is likely to die in a year instead of two years or two years and a half that you’re necessarily going to treat him differently. What we really need to do, and it’s really a challenge technically, is to do molecular analysis on the CTCs and that truly is challenging, we’re trying to do our best to do it but I really believe this is the future.


NC: John, if I might come to you and address this question of the use of androgen directed therapies before docetaxel. Where do you think we’re going to find a place for that? Should we be giving anti-androgenic therapies right up front or should we be waiting until after cytotoxic chemotherapy?

JF: As I said this morning in the discussion, I think this is the big question, this is the question that’s going to generate so much argument. Most of the evidence which suggests the use of androgen type treatment after chemotherapy, as opposed to before it, is based on laboratory based studies. There are some human ones, looking at human tissue and so on and so forth, and they, of course, are suggesting that if you use a hormone based treatment before chemotherapy you will actually worsen the response to chemotherapy. There’s a good rationale for that in that the chemotherapeutic agents act, of course, on the microtubules but they also act on the androgen receptor and this is what the problem is. So I think the answer is we don’t know yet, it definitely needs to be looked at and the phase II studies, if you can call them that, suggest that there is a clinical effect and that in fact it may be worse results to chemotherapy if you give them a hormone based treatment first.


NC: Bertrand, if I could just ask your view on this. You’ve got extensive experience of using all forms of treatment and, in particular, some of the more advanced anti-androgens – enzalutamide, orteronel and so on.

BT: My perception is the following one, is that anti-androgens, and clearly all steroidogenesis inhibitors, are for those patients we call castration resistant. In parallel to that we have patients who are truly androgen independent so I truly believe that there are clones of tumours or even patients who, from scratch, are independent or will be unresponsive to any hormonal manipulation. The problem is that we, with PSA, with bone scan, with pain, we average all the clones of a single patient and take at some time one decision for all the clones. Where, clearly, even if you take circulating cells like Karim was mentioning, if you take one patient’s circulating cells actually it’s a mixture of all different tumour types. So every patient is heterogeneous and as long as we are not able to sort that heterogeneity, either with biomarkers or with modern technology, that question will be difficult. No, as John Fitzpatrick, I’m quite puzzled by these data showing that actually the interference between taxane and androgen receptor inhibitors seems to be in favour of a chemo first, androgen inhibitor second but once again this is much more like hunting series than real data. So we need to do the proper trial because we can’t assume that just because a drug is less toxic followed by chemo it will be better. There is a problem of cross-resistance and we need to tackle that issue properly.


NC: So really what I take from that is that the question is not just one of sequencing but also one of combinations.

BT: Exactly.

NC: And Karim said earlier on that we were a long way behind certain other specialities such as breast, such as colorectal.

JF: We’re behind breast cancer in so many ways, unfortunately, and we were talking about personalised treatment, we were talking about prognostic markers, they have all of that, at the start of it anyway, and we need to develop our thought processes to go along that road. Now you mentioned the word markers earlier on, biomarkers, hundreds of millions of pounds, euros, dollars are being put into this and there are maybe two or three out there. This is a market that is swallowing up money and there’s nothing coming out of it as yet. But one has to be optimistic and hope that something will come out of it, as it did in breast cancer, in the near future.


NC: So, Karim, if I might come to you and then Heather in a sec, it leads to the question of who is going to run those trials, such as the multi-marker trials in breast and multi-marker trials in colorectal. As a leading light in an academic institution in France, how are you going to co-ordinate those trials? Should they be done in single countries; should they be done in multiple countries; how do we co-ordinate that?

KF: Well I hope we can do multi-country trials with regards to this, it’s important because, as we already said, it’s really challenging to do it. Not all institutions can do it, you need to have an access to the tissue, you need to do the medical analysis, so it has its challenge, for sure. It’s going to be mostly academic trials but still I have to recognise that in the last three or four years the industry has been quite supportive and when we conducted the COU-301, COU-302, UFER UM, some chemotherapy trials etc, many companies agreed on doing biomarker assessment either on tissue or on CTCs. I think we need to recognise that this is the way to go forward together.


HP: Absolutely and I think there are huge opportunities with some of the big multi-centre international studies that are industry funded and co-ordinated to actually include tissue samples in those because it’s a very easy addition when people are being involved in those studies to include that.

NC: Thank you. Could I come to the issue of bone targeting? Bertrand I’m going to ask you, if you wouldn’t mind starting on this, because we have firstly a two-pronged approach. One is mitigating the effects of the treatment on the skeleton and the second is mitigating the effects of the tumour on the skeleton. So if I could ask you just to start with the effects of the treatment on the skeleton?


BT: Yes, I have a very mitigated view on this which is when we look at cancer and we look at the drugs we have, we are looking at drugs that have an effect on the cancer. We must recognise that the disease itself and these drugs have a negative effect on the host. The best example is androgen deprivation therapy, then you’re taking a guy with bone metastases, you give him hormone therapy, you weaken the tumour, which is what you want to do, but you also weaken the host and you make the bone more fragile. So we have to be careful that we need a different set of drugs. We need drugs to target the tumour but we need drugs to improve the ability of the host, the patient, or the skeleton in the case of bone metastases, to carry on a longer time with the same amount of cancer. This is what we would call the supportive care area and it is funny that we recognise that for low haemoglobin, for fatigue, for diarrhoea but we have to recognise it also for the skeletal activity. That is where drugs like zoledronic acid, denosumab or even alpharadin, look at alpharadin, that’s a wonderful example: it has no effect on the PSA, it has a major effect on alkaline phosphatase, so clearly showing that it interferes with the skeleton more than with the tumour and yet it improves overall survival. So this is clearly the demonstration that we have to learn that there is the tumour, there is the host, and in prostate cancer the most important host is the skeleton and we need to strengthen the skeleton as much as we weaken the tumour. That’s where we have to put all these drugs.

NC: And Karim, from the other angle, which is the anti-cancer angle, do you think there’s a role to play for the bisphosphonates, the denosumab class of drugs, RANK ligand inhibitors, rather than just preventing bone loss from some of the treatments?


KF: I guess a direct anti-cancer effect is really difficult to prove if any. We have been debating that for ten years or so with Tosodonate??? and bisphosphonate in general; we know that this anti-cancer effect exists in the lab, whether it really exists in humans I’m not completely sure and it’s really difficult to demonstrate. With RANK ligand inhibitors like denosumab, there was also a rationale from the lab with some cancer cells expressing RANK or RANK ligand and we didn’t really see any overall survival benefit in any of these trials testing denosumab in any cancers. So it’s really difficult to do, to say whether there is any anti-cancer effect, but still it’s really striking to me to figure out that the two cancers associated with the highest incidence of bone metastases are those with expression of sexual hormone receptors, breast cancer and prostate cancer. And I think we still don’t really understand why we see such a high incidence and what is the true biology in the bone microenvironment. So we need to probably make more progress to better understand and maybe to identify new targets. Even if we don’t necessarily direct our treatment to cancer cells, if we can prevent the cells from binding to the bone, and this is maybe the story of alpharadin, we can probably do some good to all our patients in the future.

NC: Just developing and sticking with that bone targeted theme and anti-cancer effects, Heather, I wonder if you would comment on alpharadin and whether you think that that has an anti-tumour effect, given the uncertainties expressed by Bertrand and Karim, and whether, if it does, if it might be used in a combination role with other agents.


HP: I think it was one of the very good results of the last year, the results of the ALSYMPCA study and I think it does have an anti-cancer effect and it’s also perfectly poised to be combined with other agents. Obviously the big advantage of this over the other radioisotopes is that it only gives a very small area of bone marrow effect around the radioactive source whereas the others, there are great concerns of combining with chemotherapy due to bone marrow toxicity. So I think it’s sitting in a very nice position to be combined with either chemotherapy or with drugs like abiraterone.

NC: Thanks Heather, and with that exciting prospect we’ve had a wide-ranging discussion in this prostate cancer debate. I’d like to thank all our speakers for their informed comments, I’m sure there’s a great deal more discussion and a lot more work that we need to do. Thank you very much.