Prostate Cancer Debate 2014: Evolving treatment options in castration-resistant prostate cancer
Dr Cora Sternberg – San Camillo and Forlanini Hospitals, Rome, Italy
Dr Marc Rubin – Cornell University, Ithaca, New York
Dr Heather Payne – University College London, London, UK
Dr Maria De Santis – Kaiser Franz Josef Hospital, Vienna, Austria
Dr John Fitzpatrick – Irish Cancer Society & University College Dublin, Ireland
CS: My name is Dr Cora Sternberg and I’m Chairman of the Department of Medical Oncology at the San Camillo and Forlanini Hospitals in Rome, Italy. I’d like to welcome you all today to the Prostate Cancer Debate 2014. I’m joined here by my esteemed colleagues, Dr Marc Rubin who is Vice-Chairman of the Department of Oncology and Director of the Institute of Precision Medicine at the Wilde-Cornell College and the New York Presbyterian Hospital. I’m also joined by Dr Heather Payne who is Consultant in Clinical Oncology at the University College Hospital in London. Also joining us: Dr Maria De Santis who is Head of Genitourinary Oncology in Vienna, Austria and Professor John Fitzpatrick, a well-known urologist, former head of the BJU International Journal and now is actually the Head of the Irish Cancer Institute. Welcome to all of you. Today we’re going to discuss the evolving treatment options in patients with castration resistant prostate cancer. Perhaps I can start with you, Marc, could you tell us something about what’s going on today with personalised medicine and genomics in prostate cancer?
MR: We think there’s a lot going on in both areas. We’re learning a lot about the genomics of prostate cancer through next generation sequencing and although there’s a lot of new data I think one of the important findings is that we’re seeing a lot of genomic instability in prostate cancer. In the setting of precision medicine for prostate cancer, and particularly with advanced cancer, at our institute and also as part of Stand Up to Cancer Prostate Cancer Foundation programmes, we’re looking at patients in the setting of clinical trials and we’re performing sequencing to inform us as to what mutations they have and how we can possibly change the treatment and that’s a multi-institutional effort. So we think that over the next year we’re going to learn quite a bit about how patients’ diseases change over treatment.
CS: That’s very, very interesting, very interesting. I think you gave us a fantastic lecture last night and everyone was amazed by what’s going on in America and the Stand Up to Cancer and the kind of research it’s been doing. We really hope that prostate cancer will develop in the future as other cancers have by this kind of research. Heather, a lot of this meeting has focussed on the new androgen therapies and resistance to therapies. Perhaps you can give us a small overview of what we discussed at this meeting so far?
HP: Well we know that prostate cancer is a hormone sensitive tumour and we know that by reducing serum testosterone we get great responses for our patients. Testosterone can also be produced by the adrenal glands and anti-androgen drugs have been shown to block those. For many years we had hormone refractory prostate cancer and then came the finding, which is what we’ve been discussing in this meeting today, that that wasn’t the end of the story, that the androgen receptor and testosterone still has a very large part to play in managing prostate cancer. We’ve been talking about abiraterone acetate and enzalutamide. Abiraterone acetate is a CYP17 inhibitor, it has been shown to have significant benefit both before and after chemotherapy with docetaxel and enzalutamide, a very potent anti-androgen which has also shown an overall survival benefit in the post-docetaxel setting. Both of these drugs have huge promise for the future and we await the results of both of them in earlier stages of the disease.
CS: Thank you. Maria, you spoke today about chemotherapy; can you tell us now about the role of chemotherapy today and the future of chemotherapy?
MDS: Yes, chemotherapy still is a very valid and important option in the treatment armamentarium of prostate cancer, especially for metastatic castration resistant prostate cancer. In former times chemotherapy were among the first drugs that proved to be efficient. Mitoxantrone was pain relief and improvement of quality of life and then docetaxel came and was approved with an overall survival benefit. Docetaxel still is a very valid treatment option, despite there are other drugs like abiraterone or enzalutamide. So all patients at one point in the course of their disease will or should receive also chemotherapy. We not only have docetaxel, the first taxane that was approved, but now we have further chemotherapies like cabazitaxel, a new taxane, that also has shown to improve overall survival in patients progressing or having a progression after docetaxel. So chemotherapy really is important and still is important in the treatment of metastatic castration resistant prostate cancer.
CS: Thank you. John, you in the debate with Maria discussed the fact that you acknowledge that chemotherapy still had a role but you gave some strong points and arguments for why we should think about using other therapies aside from chemotherapy.
JF: Yes, I agree with Maria and with everybody else that chemotherapy still has a very significant role to play so that was not the debating point. The debating point, as far as I was concerned, was when should chemotherapy be instituted and I, like you, suggested that the concept of pre- and post-docetaxel should be done away with and that we should now look at first line, second line, third line etc. So if we now look at the position here, would we consider straight up giving chemotherapy as first line therapy. I think we all felt that probably not, that the main indication or the main thing to use would be one of the newer therapies. I pointed out that there are three treatments, new treatments, licensed in the first line apart from docetaxel, three new treatments and one potential one, depending on the results being presented next week at ASCO GU.
CS: Could you mention those, what are they?
JF: This is the PREVAIL trial which obviously all we have is…
CS: The enzalutamide.
JF: Which is for enzalutamide as a first line. We don’t know the detailed results but we do know that the press release did suggest that there’s both overall survival improvement and RPFS, radiographic progression free survival, improvement.
CS: Now, why did you mention the different drugs that we could use?
JF: The ones that are licensed are, the first one to be introduced was Provenge, sipuleucel-T. I mentioned that the results are positive, it was a positive trial, but the methodology is quite complex. It’s a beautiful methodology, by the way, but it’s still rather complex and it’s also quite expensive. The side effect profile, there is a significant side effect profile but it’s not actually a severe one and so, from that point of view, it can be considered. Unfortunately the survival advantage is not great enough, I think, to have that considered ahead of abiraterone where there is a very significant improvement in the radiographic progression free survival. There is also a significant improvement in overall survival but not enough to reach statistical significance in the trial. I mention the point that in prostate cancer we’re going to have to get used to using radiographic progression free survival as being, perhaps, certainly in the early trials, the element where we have… the benchmark.
CS: So we absolutely have a lot of new options; we’re not going to discuss pre- and post-chemotherapy, we’re probably going to discuss first line and second line. We have a lot of new options and we can decide, based on the individual patient, which of these drugs we think is best. The time to progression was not necessarily positive in the sipuleucel-T trial but overall survival was so we have to look at our endpoints a little more closely, I would agree with you on that.
JF: Yes, and I think, just to, sorry, add to that, the time to progression was not significant and the basic underlying thing was that we don’t actually know how Provenge affects prostate cancer. We know the basic way it works but how it works specifically in prostate cancer has not been defined. Sorry.
HP: I was going to say that during your talk it just… ten years since the TAX 327, the docetaxel data, came out and how far we’ve come in those ten years with advanced prostate cancer. If you look at the overall survival from TAX 327, eighteen, nineteen months, and then we’re looking at 35 months with abiraterone in that same group of patients. So we really do have a lot to offer our patients now and, after your talk yesterday, hopefully we can have even more in the future which is a good place to be.
CS: I’m convinced that what’s happened is that oncologists and neurologists and pathologists and radiologists started to work together and we started to be a team and perhaps we weren’t a team in the past. Only by being a team can we really have progress and that kind of progress was made because we became a team, perhaps with docetaxel, started working together and then we’ve had all these new developments. Do you want to say something, Maria?
MDS: I just wanted to add that you pointed out very nicely that when we speak about first line, second line and maybe third line and fourth line it gives a picture of what we have achieved and what we have in hand. We have multiple drugs and agents in hand and the management of prostate cancer has really changed a lot for the last five or six years. This is really very nice and a good feeling to be able to offer that much to our patients and to set the scene for the patient when we first discuss treatments with them, as seen for maybe the next five, six, seven years and this is very different from 2004 when we only had docetaxel.
CS: And we were very thrilled to have that but now we have much more hope to offer. Can I get back to metastatic castration resistant prostate cancer again in patients who have had chemotherapy? Perhaps, Heather, you can discuss a little bit about the results that we’ve achieved after chemotherapy?
HP: Again with abiraterone and with enzalutamide both showing four, five months improvement in overall survival which is huge for a group of patients, as you said, we felt lucky to give them docetaxel. But having something else to offer after that has been a great step forward. But the important thing, perhaps, is that there is not just an overall survival benefit but there are significant benefits in pain control, in quality of life and these drugs being oral compounds are easy to take and patients are able to get on with their lives. They have an overall survival benefit and the general improvement in lifestyle is a wonderful thing.
CS: Heather has mentioned quality of life, I’d like to ask each one of you, I’ll start with you, Marc, what do you think about the importance of quality of life for our patients and in these trials that we’re conducting now, these new agents?
MR: Obviously it’s a very important factor, we heard about that during the course of the conference and it just reminds us that, whether it’s in clinical trials or with individual patients, we have to think about what are the effects of any of the new agents on the individual patient and what can the physician do to try to improve the quality of life?
CS: Maria?
MDS: I think quality of life has been underestimated for many years and the voice of the patients has not been heard for many years. Now, in most of the trials quality of life measurement is implemented and evaluated prospectively. This is a great achievement that reassures us that we are doing something good for our patients, not only improving overall survival but also improving their quality of life, their pain and how they function etc. So it’s a very important achievement in the recent trials, I think.
CS: John?
JF: Oh, absolutely agree with everybody. At this stage of the disease I think the most important things are improvement in quality of life and relief of pain. Survival benefit is actually, at this stage, probably of secondary importance. Increasingly though, what you’ve just said, Maria, is true in that people doing trials are realising the importance of all of this and patient reported outcomes are now de rigueur. In fact there’s a new group, from Harvard University actually, ICHUM, which is looking at patient reported outcomes and trying to get a minimal dataset relating to how patients feel. The outcomes from this particular study are going to be published somewhere reasonably soon in the United States so I think this is a very important question, yes.
CS: I think we’ve all become much more sensitive to quality of life and that’s very important to all of us. Let me just ask one final question to all of you, I’ll start with you, Marc. If you have a crystal ball what do you think the future holds and what kind of trials should we be thinking of for the future to help our patients?
MR: We’re hoping to see informed trials based around genomic alterations and so that’s something that we’re very interested in. One of the important implementations that have occurred, really, in precision medicine we discussed during the meeting was following patients with either circulating tumour cells, more invasively with biopsies, but nonetheless following patients along the course of their treatment, I think that’s going to be very important and it will allow us to manage trials differently, I think.
CS: Heather?
HP: I think it’s hard to argue with that or to think of anything else that would be more exciting for the future but one of the other topics that has been brought up during the course of this meeting is sequential therapy versus using multiple agents together. And certainly in other tumour types or in other diseases using multiple agents has been very beneficial in that you may delay resistance to drugs. So sequencing studies and giving drugs together are going to be something that’s happening at the moment and those results will be very interesting and may change our practice but, of course, will come at a cost, both a financial cost and perhaps a side effect cost to patients.
CS: Maybe even cure if we’re really lucky. Maria?
MDS: I totally agree. I think the major questions should be answered in very smart clinical trials looking for resistance mechanisms and trying out combination therapy. On the other hand, implementing our knowledge about genomic alterations and making specific trials with targeted agents that might work in patients with specific genomic alterations.
CS: John?
JF: I think we have to look forward and the personalised medicine thing is the way forward. However, having said that, one of the things associated with personalised medicine and you alluded to this, Marc, is the cost. There is, at the moment, a huge inequality in cancer treatments available to the world and this will get worse, unfortunately, unless the cost element of what you’re doing, the fantastic work that you’re doing, unless that’s taken into account. You’d like to see this made available not only to people in New York City but to people in less affluent parts of the world. I say that not to be sanctimonious but just to say that it is a reality and if you would ask me to look into the crystal ball that’s what I would hope to see.
CS: Do you want to comment on that?
MR: Just to say that the many, many hundreds of millions of dollars the first genomes cost to sequence and now that we can do it for near a thousand US dollars, that I hope that, and being optimistic that, in the future this will be less expensive and affordable for wide varieties of individuals.
CS: Thank you. I want to thank all of my esteemed colleagues and I think we should end on this optimistic note this prostate cancer debate being held here in Rome 2014 and I’d like to thank you all for ecancer.tv.
