Evolving treatment options in castration-resistant prostate cancer
Professor Gordon McVie - European Institute of Oncology and ecancer
Professor Johann De Bono – The Royal Marsden, UK
Professor Bertrand Tombal – Cliniques Universitaires Saint Luc, Belgium
Professor Juergen Gschwend – University Hospital Rechts der Isar, Germany
Dr Maria de Santis - Vienna Hospital, Austria
GM: Welcome to a symposium in London on castration-resistant prostate cancer, I used to call that hormone-resistant prostate cancer, it’s castration-resistant prostate cancer. Things have happened in the last five years which I haven’t seen in the cumulative 35 years before that as a medical oncologist. I’m Gordon McVie and I am the Managing Editor of ecancer. Thank you for coming, where are you from?
MS: I’m from Austria, I’m a medical oncologist from Vienna from the Kaiser Franz Josef Hospital and I’ve been dealing with GO cancers for some time.
GM: Not as long as me.
JG: My name is Juergen Gschwend, I’m a urologist coming from Munich Technical University in Germany.
BT: Bertrand Tombal, I’m a urologist from Brussels, Belgium mostly dealing with prostate cancer.
GM: And Johann?
JDB: I’m Johann De Bono from the island of Malta and I work at the Royal Marsden in London.
GM: So this CRPC stuff, OK, it’s a new dawn I think I would say, as somebody outside the field, is it a rarity, is it an unmet need or is it a common situation?
MDS: Castration-resistant prostate cancer is common and patients historically have a very poor survival, they had a poor survival with only one to three years. Also, hormone treatment is highly effective and we do a lot of hormonal manipulations in these patients. The refractory patient lives only for a short time and there is a real unmet need for novel drugs and novel treatment options.
GM: Does this disease go faster after resistance to a hormone develops?
MDS: Well yes, it goes faster. Many patients are on hormone treatment for a long time, responding for many years, but eventually every patient becomes refractory and would no longer respond to hormone therapy. Usually patients develop metastases and symptoms, symptoms mostly from bone metastases. Patients have bone pain fractures and other, we call it, skeletal related events with the necessity for surgery, for example, in spinal cord compression. So these are serious symptoms and the quality of life of these patients is not good at all.
GM: It’s not good and it’s short, that’s the bottom line.
GM: The biology is changing, got any insight into that – why? Can you measure it? Can you predict it?
JG: It’s all about PSA in this stage because the people stay on a low PSA level for a long time on the hormonal treatment, even when they have metastatic disease. But at some time when the tumour gets castration resistant, the PSA increases, increases slowly and slowly, but afterwards it increases faster and this is the first problem that is realised by the patient. Later on metastasis develops and pain develops but PSA is the first sign.
GM: Have we got nothing better than PSA as a marker? Have we neglected the biomarkers and the biology so much?
JG: PSA is the mostly used marker, it’s the best marker we still have for prostate cancer. We have some other markers on the horizon but these markers are more for diagnosis of prostate cancer but not for monitoring of prostate cancer. There’s a lot of discussion about the value of PSA in detecting prostate cancer but this is for locally confined prostate cancer. But for the advanced stages PSA is still the best marker.
GM: Now there are hormones and hormones.
GM: Tell me.
BT: There’s hormones, hormones and OUU hormones. Hormone therapy was just seen as a treatment for very advanced cancer, now as urologists we try to maybe think more about castration-resistant the day we make the diagnosis, meaning we’re really trying to improve our classification from the beginning, isolate the population of patients who are really at risk of getting castration-resistant one day and trying to implement a multi-treatment approach, combining surgery, radiotherapy in patients who ten years ago were left to hormone therapy alone. It is very seldom today that you do just castration, so that’s for those whos’s got hormone. The second is that we had basically only two classes of drug for the last thirty or forty years, we had LHRH agonists that mimicked castration and we had anti-androgen plus all the other drugs, general drugs, such as steroids or adrenal inhibitor and angiogenesis inhibitor. Now we have a new class of drug, we have LHRH antagonists which give a new view on that agonist thing we use; we’re starting to get interesting treatment. So beyond those very new, sexy drugs that are developed and implemented in very late stage disease, there is also a lot of work which is done earlier in the disease by developing new drugs for the first line treatment. Where I’m convinced is that it will be the combination of these two approaches at the beginning and at the end, when we’re going to move these drugs earlier on in the disease we’re going to see the big improvement.
GM: Maria, you showed a slide and asked the audience to vote on five options for treating somebody of my age, a 67 year old man with metastatic castration-resistant prostate cancer. I was amazed there were five options, Johann, this has crept up on me. We’ve got cytotoxics, we’ve got targeted radiation, we’ve got abiraterone and other subsequent anti-androgens, where did it all come from?
JDB: It’s been really unprecedented, in two to three years we have five positive phase III trials when in the thirty years before that we had one positive phase III trial for survival that really influenced the field. I think it’s come partly from really carefully designed trials that have yielded fruition but also from an increased understanding of the biology and this is work that really dates back since Huggins, really, Charles Huggins in the ‘40s, through Labrie in the ‘80s and Jim Mohler did some beautiful work showing that in men who had no testicular function their prostate was still full of hormones; really seminal work from Charles Sawyers’ group showing that the AR remains really key to driving this disease. And I guess now our work with abiraterone, our work with MDV310 has really shown in these big phase III trials a survival benefit, so really confirming that those other studies were correct, that actually this cancer is not hormone refractory, is not hormone resistant, is not androgen independent but truly remains hormone driven. And it is likely that even when these patients progress on abiraterone or MDV3100, the cancer is probably still hormone receptor driven. The cabazitaxel trial, I guess, was more traditional drug development, although there is increasing evidence that cabazitaxel and docetaxel are not traditional chemotherapies but are actually drugs that are targeting androgen receptor signalling, particularly impacting tubulin’s role in the cytoplasmic to nuclear shuttling of the androgen receptor. The Sipucel-T work with this cellular active immunotherapy is very interesting and is probably one of the very first trials that has been positive with any kind of immune therapy in treating advanced cancer but I think this whole area of immune therapy is going to be probably a rich scene for us to mine in the near future.
GM: Now, the audience answered to your choice of five things, first off, cytotoxic, right? And you went with that.
GM: So that’s your first choice and not everybody agreed with you, I have to say. But that’s in your view the first choice and that would be docetaxel or the carbotaxel.
JDB: So that’s based on the evidence we have to date.
GM: At the moment, yes.
JDB: However, we have evidence that drugs like MDV310, abiraterone are highly active pre-chemotherapy. So we currently cannot recommend these drugs pre-chemotherapy as yet until the phase IIIs actually read out. But, based on the cancer biology, based on the phase II trials in this disease before chemotherapy, in fact these drugs are more likely to be even more active pre-chemotherapy. And in fact, like Herceptin, these drugs may have the most important role in the adjuvant treatment of patients with prostate cancer, where people like Bertrand, I’m sure, will drive, showing that these drugs improve survival and cure rate in men with earlier stage high-risk disease.
GM: Now your phase III data was really remarkable and I was particularly struck, going back to your quality of life and the bone disease and so on, in terms of advantage for abiraterone, in this case on time to SREs, to bony disaster, because that’s how it usually goes. So you can see this drug moving up to an earlier phase, that seems to be clear. We don’t have a HER2 new, an ERB2 for androgen.
JDB: We’re working on it.
GM: So what’s the…?
JDB: So there is evidence that these S gene rearrangements are hormone driven and may actually help us predict the patients that benefit most. The caveat to that is there are patients who are rearrangement negative that actually do have some benefit but we have published evidence in Cancer Research that actually the patients with these rearrangements are the most likely to benefit and these are genetic chromosomal rearrangements like BCR-ABL in chronic myeloid leukaemia that actually result in a potent oncogene becoming hormone driven. So we have some evidence for that and we need to do more work in that area and that work is on-going.
GM: I like the way that a lot of your audience also voted for clinical trials and that’s so clearly… there is an increased enthusiasm, an optimism about oncologists’ and urologists’ approach to this whole disease. What are the next bunch of trials going to be? Are you going to be looking at head on cytotoxic versus abiraterone; are you going to be looking at combinations; are you going to be saying OK, abiraterone’s clearly in its terms of side effect profile much preferable to docetaxel? What about the length of the drug, how do you keep on going? You did ask this question, if you carry on with this drug after a year, PSA is going up but the patient is feeling fine. What are you doing at the Marsden?
JDB: So I think to look at the most important questions, and I go back to this issue, adjuvant therapy with abiraterone is going to be key. If I had to name one most important trial…
GM: That would be it.
JDB: That is the key trial because I think it will increase cure rates, I hope.
GM: And that’s for the urologists because the medical oncologists often don’t get in there yet...
JDB: Well I think, to be fair, we’re working in partnership.
GM: Are you? OK.
JDB: And I hope that that will be the case as we move forward and I would actually recommend to any patients listening to this that actually they should see physicians that are working in a team that involve both an oncologist and a urologist and Bertrand, I think you would agree with that.
BT: Yes, unfortunately across Europe there are not many countries where multidisciplinarity…
GM: Is practised.
BT: There are some countries where it’s still mono-specialist and this is the main threat to the development you are now quoting, is that we will achieve if we work together otherwise…
GM: And in your country? MDTs? You work together with each other?
GM: You work together with the lab people developing biomarkers, with the imaging people?
JG: Absolutely, so in Germany we have a strong collaboration between urologists, oncologists and radio oncologists as well as basic researchers to develop treatment, and mainly in this create bigger cancer centres. So I guess that all over Europe we have several places where we work pretty good together.
GM: And Austria?
MDS: Well, we used to work interdisciplinarily and in multidisciplinary teams and we used to discuss nearly all patients in tumour boards where urologists, medical oncologists, radiation oncologists, pathologists are present. So this is a very good forum to discuss patients and it is really multidisciplinary.
GM: I’m struck by Anwar Padhani’s talk on imaging and defining, as best as possible, where you go with particular strategies and also how you define whether you’re achieving anything or not. He was pretty critical of us urologists and oncologists using bone scans now and he was saying the time for bone scans is out, now we’re talking about PET for soft tissue and this new DWIMR, the magnetic resonance imaging, the cheap and cheerful quick imaging technique to measure response and progression. Particularly, of course, he works with you, Johann in new drug development.
JDB: I think the first thing to say is that bone scans cannot distinguish healing bone or fractures, for example, or what we call osteoblastic reaction in the bone from tumour. Not only that, but if you give drugs that are highly active, like abiraterone, the bone scan can look worse in what we call tumour flare.
JDB: So to measure response, bone scans are not particularly useful, particularly in patients with very advanced cancer where the scan is what we call a superscan. But actually for determining the presence of metastasis in very early stage disease, bone scans have utility. But I think what Anwar is trying to say is that for very late stage disease, if we’re monitoring response, bone scans have very little utility. Diffusion weighted MRI requires some very careful evaluation, sadly those trials are going to be very expensive and will not be funded by the drug industry and we will have to get federal or charity funding to fund these large and expensive trials that will cost probably €50 million or more to really prove that these new methods of imaging are actually better than the established or actually unproven but established imaging methods.
GM: Germany has got the money, are you going to do these studies?
JG: Yes, we do these studies but not on a large scale basis and this is the problem. So I guess we do all agree that the bone scan is old-fashioned imaging and that it often does not tell the truth. But on the other hand we have the problem that, for example, for PET scanning we have a lot of PETs done all over Germany and Europe but we do still not have any strong evidence that PET imaging is good for prostate cancer, for primary diagnosis or for monitoring. And the same is with MRI, so MRI could be done but it’s not proven that it’s really helpful. So this is my criticism.
JDB: What we need is regulations that actually control and define how these drugs become… sorry, how these modalities of imaging become widely utilised. Approval mechanisms for imaging.
GM: But we need to drive that as the consumers of those imaging, in my view. Whoever compared, in a randomised trial, CT versus ultrasound in liver metastases? It has just never been done. So there is not a history or a tradition of doing randomised trials to develop the evidence base in imaging.
JDB: That should change, that should change.
GM: But that has to happen now. Now what happens in Belgium?
BT: In Belgium we have a large number of MRI and all groups already publish in 2007 in The Prostate which is a good paper among urologists. Actually you can apply RESIT criteria on bone mets. We went to several companies, nobody is interested to evaluate this. Why? Because everybody is pleased by still using bone scan and its un-appropriateness. So everybody quotes also a problem of cost, it depends from country to country. When you see, for instance, whole body MRI as shown by Dr Padhani today, it is advertised by many centres not as a way to make diagnostic but as a way to make money. So we have to realise that behind modern technology there is also a hype and we don’t know where is the limit between true breakthrough science. Because there is always a risk of changing the way you categorise the patient. Let’s say you’ve got a young guy, 65 like you, very young guy.
GM: Thank you.
BT: And you find a prostate cancer, quite aggressive, and you say, “We think about radiotherapy, hormone therapy.” Then suddenly instead of a bone scan you do an MRI and you find a 1cc bone met and because of that you say, “No, I’m not going to give prostatectomy.” So we need absolutely to find a way to test this and I think the only way is to go to work with regulation authority and force industry to invent this technology in the trial.
JDB: We need to regulate this imaging modality utilisation.
GM: I’m sure it has to come but it will come a lot quicker if people like you encourage it. I was also impressed, to go back for the last time, to your very illustrative patient which you showed, when the issue of age came up. Now, a sensitive issue, most lay doctors would say advanced metastatic prostate cancer, that goes with an age of 80 and therefore that goes with palliative care full stop. I think, Johann, you said something very clear and it’s an issue that we have to confront in our bias which is an ageist bias. In haemato-oncology we ran a meeting in Rome last year and it was rampant, in prostate cancer it’s also a preconceived notion and we must get rid of that because the kind of studies you’re doing show actually age isn’t a factor, it’s performance that’s a factor.
JDB: Absolutely. I think first of all prostate cancer is not a disease of old men, or older men even. There are a lot of men with prostate cancer that are under 65, this is not that different to breast cancer. But importantly age should not impact how we treat the patient, the benefit is still the same and I think ethically, morally and clinically and from a research perspective age should not matter.
GM: Thank you. Any other last words? What’s going to happen in 2013? Bertrand?
BT: I would say nobody could say it because nobody could have anticipated in 2003 that we would have had that symposium today. So I would be very careful about that.
GM: That’s very careful, very good.
JDB: We’ll have some exciting new drugs coming through, other drugs. Cabozantinib is looking very promising in this disease; the AKTPI tri-kinase inhibitors are looking very exciting. Combinations of the drugs we’ve discussed today like MDV310 and abiraterone, the ARIG and the AR inhibitor is new, we are targeting drugs that degrade AR. It’s an exciting time.
GM: And the other immunotherapies like ipilimumab and that whole…
JDB: Ipilimumab, it’s very likely that trial will be positive, I agree.
GM: Any other last thoughts?
JG: I guess we have an exciting time in prostate cancer, especially for castration-resistant prostate cancer. We have seen this with renal cell cancer, let’s say five to six years ago, we have it now with prostate cancer and this is exciting to me.
GM: Yes. Anything? Last words?
MDS: Last word, well I think we are approaching even more exciting times than we have now. It is wonderful to have a lot of drugs for our prostate cancer patients and I’m really waiting for data of the on-going trials or trials that have finished accrual to have new data and hopefully more drugs.
GM: So the bottom line is that you should be putting all your patients into prostate cancer trials. Thanks very much for all your wise words and your enthusiasm which comes through. Tremendous, thank you.