Speaker key

JB        Joaquim Bellmunt

NM      Nicolas Mottet

AB      Alfredo Berrutti

NC      Noel Clarke

JB        Welcome to ecancer.  We are here in Vienna to have this interesting roundtable discussion about recent advances on the treatment of castration resistant prostate cancer.  And it’s a privilege to introduce the panel of speakers we have here.  We have Dr. Nicolas Mottet, from Saint-Etienne, we have Dr. Berrutti from Italy, and Noel Clarke from Manchester. 

The aim of this roundtable will be to discuss the options we have in the post-docetaxel area, where patients in the past patients didn’t have any treatment option.  And nowadays, we now have several drugs approved, and more drugs that are coming, and we need to know how to manage and how to best implement these treatments for our patients. 

So let me start by addressing the first question to Professor Mottet.  Can we update a little bit on the recent advances we have seen in the management of castration resistant prostate cancer nowadays?

NM      Well, a lot of improvement.  We have at least three positive randomised trials showing an overall survival improvement.  One is a new hormone treatment that showed that even if the prostate cancer is considered to be progressive after ADT, it’s still overly sensitive, it’s androgen driven, and that’s with abiraterone, which showed an overall survival.  The second is a totally different drug, a chemotherapy, the second taxane inhibitor, cabazitaxel, which showed, again an overall survival improvement.  And the third one that will appear very soon but there was a press release over a month ago, was with the MDV, again an anti-androgen drug that showed an overall survival improvement. 

These are the three main drugs that showed an overall survival benefit.  And apart from these three drugs, there was another fourth one targeting specifically the bone with an alpha-inhibitor drug that showed also an overall survival improvement.  Now we have a lot of tools to treat patients that are progressing after docetaxel.  The question is how do we define patients for each individual drug, and how do we combine them, or not?

JB        So this is the important message:  how are we going to use these agents.  The trials were not designed just to address a specific therapy for a specific patient population.  And nowadays we have approval for this second line, after docetaxel, we have two drugs:  we have abiraterone, that is an oral compound.  And we have cabazitaxel.  So based on that, we need to define who is more suitable for chemotherapy; who is the best candidate for this new hormonal therapy.  So Professor Berrutti, what do you think on that?  How can we define a patient being high risk? 

AB      This is of course an important question, the crucial question, because on this basis we can define which is the best treatment for each patient.  So of course the treatment should be chosen on the basis of predictive factor that we don’t have yet.  So prognostic factors maybe actually the most important tool we have to define the best strategies. 

A common opinion shared by many oncologists is that, well, if the tumour displays very aggressive disease, displays signs of aggressiveness, this tumour should be treated with chemotherapy.  Chemotherapy should be preferred than hormone therapy.  And this is true, we can share this kind of assumption.  How to define patient with greater aggressiveness?  Well, we have some markers.  We have nomograms.  As an example, these markers are LDH, lactate dehydrogenase, alkaline phosphatase, it is a bone marker of osteoblast activity.  PSA.  Bone pain is an important issue.  So on this basis, we can make a choice.  Another important point is the Gleason score at diagnosis.  High Gleason score leads to a more aggressive disease. 

These are the tools we have to properly define the patients that should be candidates for chemotherapy with respect to abiraterone therapy.  But in terms of percentage, we don’t forget that androgen receptor is the main target, so the majority of patients should be addressed to androgen deprivation therapy and abiraterone, and only a minority should be addressed to chemo.

JB        So going to daily clinical practice, Professor Clarke, we are going to have these two agents available, and probably those agents will be used sequentially, so cabazitaxel first followed by abiraterone, abiraterone followed by cabazitaxel, in some of the patients.  How can you define the patient profile who will be more suitable for receiving, for example, cabazitaxel first, followed, maybe, with abiraterone?

NC      I would look at the risk profile, firstly of the cancer, but also of the patient.  Dr. Berrutti has mentioned some of the cancer-related aspects of risk.  I think it’s important also to consider the clinical aspects of risk, in particular the co-morbidity of the patient, the age, what the individual’s life expectancy is and so on.  So if we consider cytotoxic chemotherapy in the form of cabazitaxel, where we know that there was a positive survival advantage from the treatment, we also know that there was a significant toxicity profile; about 8% of the patients got neutropenic sepsis, for example. 

So if we were to consider the patient who might be suitable for cytotoxic chemotherapy, I personally would be looking at the fitness of the individual, the age of the individual, I’d look to see what kind of response they got to docetaxel in the first place.  We know that people who have responded well to docetaxel will often respond to a secondary challenge with a taxane, whether that’s docetaxel or cabazitaxel, and make an assessment of whether the risk benefit ratio was appropriate to go forward with a cytotoxic chemotherapeutic agent. 

The other side of the coin is the secondary hormone manipulations with abiraterone acetate.  That doesn’t have the toxicity profile of cytotoxic chemotherapy, but it does have a toxicity profile in itself.  We know that the patients who went into the 301 study, that’s abiraterone acetate and steroid, versus steroid given alone, had a positive survival benefit.  But we also know that they were predominantly good performance status patients, and we don’t yet know what the cardiac toxicity profile in the general population is going to be. 

So on the whole, there’s a perception that the hormone treatment is going to be less toxic than the cytotoxic chemotherapy, and I think probably that will be true.  And that will drive elements of decision-making. 

There is another factor, and that is who sees the patient.  In many circumstances, urologists will see the patient as their first port of call, and urologists are quite comfortable with hormone treatment, but not necessarily comfortable with cytotoxic chemotherapy, and that may also be an element which comes into the mix of who gets what.  So I think it’s, in summary, important to look at the patient and see what is best for the patient in terms of risk profile, the potential for benefit, and then choose accordingly whether chemotherapy is the best, or whether hormone therapy will be better given first.

JB        So in addition of the factors you have been mentioning, Professor Mottet, we have not talked about the role, as a prognostic factor of pace of disease and PSA doubling time.  Do you think that, in addition to taking into account all the factors that have been mentioned, pace of disease and PSA doubling time plays a major role?  Or that we do not have data for that, so we are assuming that those might be important. 

NM      Those factors are prognostic factors, which means that when you have visceral mets and a very short PSA doubling time, about 30 days or less than 50 days, you are in a very poor prognosis situation.  That’s proven for the docetaxel-treated patients.  What is not proven is if these factors are predictive factors.  It’s totally ignored.  We don’t know.  We have the feeling that patients with mets on the liver, visceral mets, have a poorer overall evolution compared to patients with bone mets only, but what is totally ignored is if these patients require second-line chemotherapy, if they are able to receive it, or if the second-line treatment should be hormone treatment. 

We know the patient has a very poor prognosis situation, but it’s not the proof that they should have second-line chemo first.  So, it makes sense to believe that the most aggressive disease might be treated with second-line chemo, especially if they had a very short first-line response with the first-line ADT before docetaxel, but it’s just a feeling, it’s not evidence-based so far.  So very short PSA doubling time, visceral mets, very poor prognosis.  It’s not equivalent to strong arguments for second-line chemo. 

JB        So excellent.  Presently we do not have the data on how to decide.  We have assumptions.  Excellent discussion you have done. 

But the field doesn’t stop here.  We have more drugs that will become available.  We have heard that we had two additional positive trials.  We have MDV, that is also a hormone compound, with a different mechanism of action than abiraterone.  And also we have alpharadin, that is a bone therapy that is already a pharmaceutical using alpha emission instead of gamma emission that used to be used in the past. 

So Professor Berrutti, how are we going to integrate an agency like MDB in the management of our patients?  Are we going to use it before abiraterone, in combination with abiraterone, after chemotherapy?  Let’s guess how we’re going to manage all these compounds in the future.

AB      Yes, MDV 3100 is a really very important drug, and similarly to abiraterone has obtained a survival advantage in patients pre-treated with docetaxel.  So MDV will, in the future, be among the drugs available.  So, how to integrate MDV with other drugs we’ve mentioned before. 

Well, the mechanism of action is totally different.  MDV is a small molecule targeting androgen receptors.  Androgen receptors, in prostate cancer, is an oncogene.  Androgen receptor is the main target.  So MDV has a strong impact.  And, of course, the mechanism of action is complementary with respect to abiraterone, which main effect is to reduce, consistently, the androgen, and in particular testosterone.

I can imagine, of course, the possibility to combine the drug.  With respect to the sequence, I don’t have a clear idea, but probably nobody has, which is the best integration you expect.  But what I think, generally speaking, I agree with Christopher Logothetis who published recently a review article focusing the attention on the fact that, for effectively treating prostate cancer patients, we have to consider and we have to target not only the cells, as an example, targeting androgen receptor, but also the macro environment.  I mean, testosterone levels and so on.

In this respect, alpharadin is a new drug that could do something in this scenario, because alpharadin is a bone targeting agent, and we know prostate cancer patients very frequently have metastatic bone disease.  And bone macro environment is really very important in terms of disease progression and the stimulation of spread within bone marrow.  So alpharadin targeting the bone marrow and reducing the bone turnover can be complementary with respect to hormone therapy, and I personally believe that the association of currently available drugs can improve the efficacy of alpharadin administered alone. 

JB        OK.  Having all these drugs available, one of the decisions will be a patient is going to receive docetaxel, at some time point the patient is going to fail the therapy, and we need to decide to switch to one of these therapies.  And whenever we are deciding just to prescribe abiraterone, a decision will be when to start.  Are we going to start based on a PSA increase in symptomatic progression?  How are we going to monitor the efficacy and the toxicity of abiraterone when being prescribed in this setting?

NC      Well, that’s a good question, because the threshold for initiating therapy in the mind of the clinician in relation to the patient is often dictated by, as I mentioned earlier, risk benefit.  So if one’s considering cytotoxic chemotherapy, either re-challenge with docetaxel or new challenge with cabazitaxel, one’s always conscious of the potential for side effects.  And so most clinicians would wait until the patient was symptomatic, or, on occasions if the PSA was rapidly changing, consider stepping in at that point.

With the newer hormone therapies, abiraterone acetate, MDV 3100, the side effect profile is correspondingly lower, so in my view the threshold will be much lower for initiating treatment when patients are exhibiting signs of progression.  So when the PSA is starting to go, or whether there are new bone metastases on bone scan, for example, then that might be a driver to initiate a second-line hormone therapy.

Now, that’s not to say these newer hormonal agents aren’t without their toxicities, because clearly drugs like abiraterone acetate to have effects on metabolic profiles, in particular, related to steroid and mineralocorticoid effects.  So it’s important to be cogniscent of the fact that in a patient with medical co-morbidity, cardiac arrhythmia, ischemic heart disease, and so on, one has to balance the potential for initiating a non-cancer problem as a consequence of starting treatment.  It’s a real possibility.

So these other things will go into the equation which will drive a decision to start treatment.  But overall, my opinion is that hormone therapies will be started sooner than cytotoxic chemotherapy. 

JB      Thank you very much, Professor Clarke.  So we have seen that we have so many options, fortunately, for the patients in this post-docetaxel setting, however we have a lot of questions still that need to be answered.  We don’t know about predictive factors.  We are here discussing, we are urologists and oncologists trying to make decisions and to decide what is best, what’s the patient profile more suitable to receive abiraterone or cabazitaxel.  But also because of these new agents that are going to come with perhaps alpharadin or MDV 3100, that the field is going to be more and more complicated. 

We hope that in the future we are going to have prognostic and predictive factors, but what we can say here is that in this roundtable we have been addressing the potential arguments to defend one or the other treatment and how to monitor the management of our patients. 

So, with that, I would like to thank you very much for your contribution to this roundtable discussion, and hopefully we’re going to have more data to provide, in the future, more strict recommendations on which agents need to be used in different situations.  Thank you very much.