Attendees:
Professor Noel Clarke
Dr Heather Payne
Professor Sergio Bracarda
Professor Peter Mulders

Professor Noel Clarke
Welcome to Barcelona to the Janssen sponsored Prostate Cancer Debate.  I am joined today by three experts in the field: Peter Mulders, Professor of Urology at Nijmegen in Holland; Professor Bracarda from Perugia in Italy; Heather Payne, Medical Oncologist from London, and myself, Noel Clarke, Urologist from Manchester.  We are going to discuss some of the issues that have been raised in the prostate cancer debate, and I am going to start with Peter Mulders.  Peter, we opened the proceedings with questions about measuring end points in clinical trials, and this is a fundamentally important area not only in the assessment of new agents, but also in guiding clinicians and treatment.  Would you like to comment on your view about end points, particularly in relation to the 302 abiraterone study progression free and overall survival?

Professor Peter Mulders
In the 302 where abiraterone was given in a pre-chemotherapy setting, the end points are very important to define; of course, the end point in overall survival is the most crucial one, but, on the other hand, it depends on the mode of action and the stage of the disease at which you give the drug.  Therefore, in prostate cancer patients, in castration‑resistant prostate cancer, in metastatic castration‑resistant prostate cancer, other end points are then important, like progression-free survival, but also the end points of time to skeletal‑related events, pain development, are important end points.  It is not that you can decide overall survival as the most important one, but other secondary end points are important to take into the decision.

Professor Noel Clarke
Professor Bracarda, in clinical practice the measurement of response in a patient might follow the lines of a clinical trial, but equally there are other measures of response that you might use, and other urological oncologists might use, to determine treatments.  How might this translate in a practice like yours in Italy?

Professor Sergio Bracarda
In our situation there is no real difference, because for years we have worked in multidisciplinary teams in prostate genital urinary units, and we follow the patient from the beginning, together with the urologists.  I am a urologist and I am also an oncologist, and I frequently work with my colleagues from the beginning; there is no translation of this patient from their hormone therapy to the [inaudible] second‑line hormone therapy or chemotherapy: we decide together.
With our radiotherapy colleagues, we make the best choice for the patient at any time during their natural history.  With the availability of these new oral pills, it does not make a difference in the local situation, when there is a sequential treatment option; from urologists and oncologists it is possible that the cut-off could move from hormone therapy to chemotherapy.  That is the recent situation to [the actual?] and the situation with the movement of the patient from one to the other, because abiraterone and enzalutamide could be prescribed and used from both of these specialties.   What is really important is that the physician that follows the patient is able to understand and able to treat the patient with the new drugs.  The type of specialty is less important with respect to the competence with which the patient is treated.

Professor Noel Clarke
Developing that theme, Heather, you have got a very active and interesting MDT process at UCL in London, where you have a number of urologists, medical oncologists, clinical oncologists, and other associated cancer healthcare workers.  How does it work for you in your setting?

Dr Heather Payne
At the present time it works very well, and the multidisciplinary team is probably the key to ensuring that patients have all options.  The clinical nurse specialist is also a very important person in the multidisciplinary team, and perhaps an intermediary between urology and oncology.  The most important thing, and we live in exciting times with these new drugs, is that every patient has access to the drugs that could potentially be of benefit to them.  Looking at end points, real life can be different to clinical trials.  Sometimes, in a lot of hospitals, we are not doing scans every three months as you would in a study; you are not doing the same sort of investigations.  Clinical progression: if we look at PSA, radiological, and clinical progression, clinical progression perhaps is the most important one from the patient’s point of view, in order to change treatments, but also using the other parameters to try to predict disease that is going to become more aggressive, because obviously we want to be one step ahead of the cancer.

Professor Noel Clarke
You made a very interesting point early on in the discussions that one of the things you looked at, and was one of the most important factors, was how well the patient felt, which is a somewhat nebulous concept, and trying to put an end point on that is not always easy.  For you, that is a really important issue.  From what aspect of the patient’s wellness would you say you look at; is it just how they look, or how their social life has been affected?  What is it that you look for in a patient?

Dr Heather Payne
Well, obviously it is symptoms; symptoms from the disease and symptoms or side-effects from the treatment: if somebody has no pain and no toxicity from their therapy and is enjoying a good quality of life, and hopefully a better quality of life from when they started the therapy.  It is the chap who comes in and says, ‘Yes, I feel well.  I have not got any problems or complaints.  I would want to continue with that treatment’, despite the fact that perhaps there would be one slight little extra rib metastasis or the PSA was going up slightly.

Professor Noel Clarke
Peter, can I come to this question of sequencing, because that has been a feature of the discussions throughout.  We have touched on the multidisciplinary approaches; in some countries urologists will give cytotoxic chemotherapy, in other countries they will not, but in most countries they will give hormone therapy.  In a practice like yours, where you will actively give cytotoxic chemotherapy, what colours your decision regarding sequencing? 

Professor Peter Mulders
There is a change to what we had, and what Heather said: what is a multidisciplinary team?  These days we have medical oncologists in the same outpatient clinic, which is crucial, because you need patient involvement.  You can present a case to other specialties, and make a multidisciplinary decision, but it is different when you see the patient together with other specialists, to make the decision together with the patient, because then you figure out what the patient wants. As a urologist you may know the patient for years sometimes, and the patient may tell you what kind of a drug he may use, and then implement that in the decision.
It does not really matter who is seeing the patient, but it is good that more specialists see the patient, together with the patient, to make a decision.  Then it becomes easier to determine what the sequence is; you need to know what these drugs are doing after the pivotal trials have been done.  If you have experience in the trial you know the difference between a patient in the trial and a patient after the trial, at a different time than when you prescribe it, because it may have a different side effect profile in that patient population.  There it becomes very crucial that you try to attract more specialists in the multidisciplinary team; I agree that case managers and nurses are very important there.

Professor Noel Clarke
We have a number of patients who we, as urologists, would suggest are not necessarily fit for chemotherapy, but how would you assess that group in Italy?  Do you think having the multidisciplinary group, with medical oncologists, results in more people getting cytotoxic chemotherapy, or are we directing more people down the line of hormone-directed therapies?

Professor Sergio Bracarda
The most important consequence of the multidisciplinary team is that you can move from the position of what I can prescribe to the position of what is in the interests of the patient, independently from the type of agent that you are advocating or not.  Of course, in our activity as a tertiary centre, we have a lot of experimental protocols; for example, currently we have 30 ongoing trials.  Our first proposal to the patient is to propose they enter a clinical trial.  If the patient is interested, we evaluate the comorbidities of the patient; frequently in prostate cancer we are treating an aged patient, with important comorbidities, especially cardiovascular and many other drugs for treating hypertension, vascular problems, and we have to consider this.
One of the other fields that should be entered in a multidisciplinary team is the pharmacologist, especially the nurse for the case management.  We evaluate, age, the general condition, the comorbidities of the patient, what could be, according to the previous treatment, the best choice for this, between effective agent, active agent, and supportive care.  In some cases, it is not in the best interests of the patient to prescribe some efficacious agent, because it increases the risks of the level of toxicity.  This means presenting very few cases, but at the end of the evaluation of the patient there is supportive care to be considered, because, from an ethical point of view, even if there is pressure from the patient to be treated, as a physician you have to consider the interests of the patient, and the possible response.
It is a classical way of understanding it.  Of all the studies, to understand that in some patients there may be performance in terms of relevant effects and disease control through use of the newer agents, even if there is a lot of exception to this.  This is your ability as a physician to identify the potential patients in poor condition that could receive an advantage from treatment: this is your task.  When you work in a team, the integration of the different competencies – for example, the [inaudible] are one of the members that need to be present in your team – means that you arrive to a clear identification of what is possible in supportive care.  The recovery of the patient from poor condition, for example, due to previous side-effects rather than the general condition of the patient, the possibility of treating the patient with hormone therapy and possible chemotherapy, especially patients with negative diagnostic[?] factors for hormone therapy.
We have not moved in a sequence of available treatment; we do not have data about the sequencing, because, as stated by Peter, the patient’s metabolic condition does not enable us to monitor the best possible treatment for this situation, at this time, to have the possible best response.

Professor Noel Clarke
You have highlighted something we would all agree, which is the most important thing is patient‑centred care.  We all work in tertiary centres, often in big cities, and one of the challenges that we all have is getting the treatment out to the patients in the more provincial areas, the smaller clinics, particularly in countries where there is a large distance for patients to travel.  Heather, how do we do that in countries: London, with a big conurbation, how do we go out into those wilder areas of a country like the UK, Italy, Holland, or wherever, so the cancer team treating a patient in those areas enables the choice for the patients to be as good as it can be?  How do we get the treatment of the patients who are treated in centres, so that the standard is as high when the patient goes back to their home for palliative care?

Dr Heather Payne
It is very difficult, and certainly in the UK we have had a hub‑and‑spoke model for some years, where oncologists who are specialising in different parts of the body will go to peripheral hospitals and will attend multidisciplinary teams there, and have outside clinics.  Traditionally the difficulty has been with chemotherapy in that some men who live a long way from the cancer centres are quite reluctant to travel in for treatments.  Perhaps this is going to be a great advantage of some of the newer hormone drugs; that for the group of patients where they have shown just as good efficacy as chemotherapy it will give them another option.  There are certain situations where patients do have to travel if they are in the group that really need chemotherapy; we have to work out mechanisms of getting them to the cancer centre, and trying to make that journey as easy as possible.

Professor Sergio Bracarda
This is my situation, because I work in Arezzo in Tuscany.  The largest city is 100,000 people.  A large number of the Italian towns in the middle are medium or small cities.  We have an articulated and flexible interaction with colleagues in the other cities, and have patients that frequently ask to be treated in our centres, but in connection with their city of residence.  We are in connection, we move the patient in our centre, with respect to the needs of the patient and the needs of the family of the patient.  This is normal for us.

Dr Heather Payne
It is a balance.

Professor Sergio Bracarda
It is an effort.

Dr Heather Payne
It is a balance between making the treatment local and accessible, but then having the expertise to give it safely when maybe you would only give it once or twice in a smaller hospital.

Professor Sergio Bracarda
It is different from Anglo Saxon cities.  Our centre is a part of the Tuscany Institute for Tumours; that is distributed in the region of Tuscany.  It is a network of cancer centres in the heart of Tuscany, and we work together, moving the patient where there are the resources for them to be treated.

Professor Peter Mulders
As a cancer centre you have to be aware of the kind of patients you get; is that a reflection of all the patients in the country?  This also depends on differences in countries.  If you are aware of that you can start collaboration with smaller centres, either via video conference, but so you get a sense of what is going on in that centre, and the smaller centres get a sense of what kinds of patients are referred.  That is important: you have to be aware of what is treated in the centre and in smaller centres, and you have to communicate.
This is a strategy, for instance, in the Netherlands that goes on and on now.  You see protocols that go out of the larger centres to the smaller centres, and then you get more collaboration and an increased quality of the treatment for these prostate cancer patients.

Professor Noel Clarke
Thank you for that.  I would like to move on to the area of bone‑related treatments, and I want to come back to end points.  There is a discussion going on, not only here, but in the wider world, about measuring end points in bone and the treatments directed at bone.  Peter, coming back to you, can you talk us through your views on the skeletal‑related event and how that might be assessed and measured?

Professor Peter Mulders
Is it different?  For instance, abiraterone is different in the treatment when you have bone-targeted therapies.  Every patient with bone metastasis needs the best support for their bone; if it is proven that these bone-targeted agents do help then it should be prescribed.  On the other hand, we do not know what the impact is with the new treatment modalities, but in general, yes, bone care is important, so it should be given.  If this is a synergism in the treatments modality with abiraterone there will be abstracts on that if this is an additional [inaudible], so we have to know that.
It is kind of a separate treatment for bone care, which adds to the skeletal‑related event: if skeletal‑related events are correlated with quality of life we should do that.  On the other hand, we should be able to titrate that; sometimes we can do that with [inaudible] measures, to see what kind of bone-targeted therapy is the best, or should be sequenced.  We have to know if it adds a worthwhile new area of new treatment modality; this should be done.

Dr Heather Payne
From the session this morning there were two things that hit home to me on end points on bones: one was this flare; that within 12 weeks of starting a new drug that you can see a flare on the bone scan and that should not stop you giving the treatment, because a lot of those patients then went on to have good responses after 12 weeks.  The other thing that is really relevant in skeletal­‑related events is clinical and radiological, because a lot of studies have reported radiological skeletal‑related events, which may have no significance to that patient at all, such as an asymptomatic fracture.
Certainly the ALSYMPCA trial, looking at alpharadin, looked at clinical skeletal‑related events with cord compression and pathological fractures, and radiotherapy surgery to the bones.  That is probably the way forward of looking at the skeletal‑related events that are going to make a difference to patients.

Professor Noel Clarke
Looking still further forward, we have the data on Rad-223 and we also have the pending report on the UK Trapeze trial looking at docetaxel, strontium, and zoledronic acid.  That data is in and will be going to ASCO this year provided the abstract is accepted, which it hopefully will be.  What do you think is the future of combination therapies directed at bone, particularly with drugs like radionuclides?

Professor Sergio Bracarda
That study is of absolute interest, of course, for a pathology where about 75-80% of the cases have bone involvement, but all should be written again in my opinion, because the new drugs, such as abiraterone and zolamide doubled the time to skeletal‑related events alone.  In this new scenario they are all bone‑targeting agents, such as zoledronic acid, denosumab, or alpharadin.  I agree that it is probably an integrating scenario, but the time to association, or the time to start this agent, should be discussed again, because the natural history of this patient from the point of view of bone lesion is completely different from what we have learned in the previous studies.  We cannot move on new trials simply looking to the past; we have to understand this new agent and the sequenicng that could arise from the availability, or using the agent in the real world, could modify in the near future for our patients inside and outside of clinical trial.
In particular, for alpharadin what should be addressed is the setting of where to place this type of resource, because neurotoxicity from alpharadin will probably be less in respect to the previous available strontium and samarium, and that should be tested in patients who, after alpharadin, will be treated with chemotherapy in the real world, outside of the registration trial.  Currently this is a problem, because in actual experimental protocols, patients previously treated with radionuclide treatment without difference, cannot be included for better alpha emitters.  In the near future we do not have the possibility to evaluate in clinical trials, in patients and in the population derived from clinical trials, patients previously treated with alpharadin.  This is a bias that we have to check for the near future, to analyse the proper setting of this really important treatment option.

Professor Noel Clarke
I would like to finish by addressing the aspects of cost, and cost to healthcare systems, because these new drugs are not cheap however we calculate those costs.  Two issues I would like to address: one is does the cost inhibit the prescription of the therapy; two, how long should we go on with the treatment when we are not sure that the treatment is working?  We might also address a third point, which is: should we give these treatments to all the patients, particularly the low performing status patients?  Peter, can I just ask you about cost?

Professor Peter Mulders
We definitely should not give these drugs in cases where it is not working.  On the other hand, we have to implement not only the cost of the drug itself, but also the cost of that patient in that situation, because if, for instance, skeletal‑related events are less abundant, if a patient’s hospitalisation is less, if pain medication is less, you have to balance that with the cost of the drug itself.  You may hope that the cost of these drugs are becoming less and less, because it will have an impact finally, and that also depends on how, per country, the cost is divided through hospitals, outside hospitals, pharmacies, etc., to have access to that.
I agree, first we should be able to have our patients access to efficient and effective drugs; that is the most important thing.  It may sound simple, because the costs are rising, but I believe we cannot only implement that in the decision when you look only to the cost of the drug itself.

Professor Noel Clarke
Given the financial problems across Europe, in Spain, Italy, UK, and so on, is that a problem in Italy, prescribing these drugs, on that basis of cost?

Professor Sergio Bracarda
Possibly yes, and possibly no, because in Italy there is a cost-sharing model between companies and the Ministry of Health; if the drug works in the patient it is the public health system that pays for the drug.  If the drug does not work in the patient the cost remains with the company.  In some cases, especially in prostate cancer, where the evaluation of efficacy is difficult due to cases of bone disease, there is a discount on the payment for the drug at the beginning of treatment.
The purpose of the system to pay for performance, to pay only where there is evidence of an impact on the disease for these cases, is really relevant, because we have this type of experience with kidney cancer.  What has changed from kidney cancer to prostate is the epidemiological entity of the problem, because kidney cancer is only 2-3% of the cases treated, where prostate cancer is a large entity in the population, with relevant impacts from the pharmacological point of view.  I fully agree with Peter about the analysis, but we have to arrive at an evaluation of cost effectiveness to address the resources for agents with a really relevant impact on prostate cancer.  The positive situation is that we have a lot of this for prostate cancer; we have a revolution on prostate cancer management.

Professor Noel Clarke
Heather, you can have the last word.  Should you give a drug like abiraterone to everybody?

Dr Heather Payne
We have a duty to be responsible.  I agree with my colleagues that we have to think carefully about prescribing drugs, be certain that that patient stands a chance of having a benefit from that drug, and stopping when it is not working.  Having said that, I would still go by my previous statement: I would like all my patients to have access to the drugs that I think are going to help them.

Professor Noel Clarke
Thank you very much.  As you can see, we have a lot of new data; the data is evolving, and with each evolution we have new questions that we need to answer on behalf of our patients.  I would like to thank our panellists for our views.  I know this is going to be an interesting scenario that will continue to develop over many years.  Thank you.