COMMENTARY

Treatment Options in Castration-Resistant Prostate Cancer

Prof. Gordon McVie, MD; Maria De Santis, MD; Prof. Jürgen Gschwend, MD; Prof. Bertrand Tombal, MD; Prof. Johann de Bono, PhD, MSc

Disclosures

May 11, 2012

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Prof. Gordon McVie, MD: Welcome to a symposium in London on castration-resistant prostate cancer. I used to call it "hormone-resistant prostate cancer"; it is now called "castration-resistant prostate cancer." Things have happened in the past 5 years that 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?

Dr. Maria De Santis, MD: I am from Austria. I am a medical oncologist from Vienna from the Kaiser Franz Josef Hospital, and I have been dealing with genitourinary cancers for some time.

Prof. McVie: Not as long as me.

Prof. Jürgen Gschwend, MD: My name is Jürgen Gschwend. I am a urologist from Munich Technical University in Germany.

Prof. Bertrand Tombal, MD, PhD: I am Bertrand Tombal. I am a urologist from Brussels, Belgium, mostly dealing with prostate cancer.

Prof. McVie: And Johann.

Prof. Johann de Bono, PhD, MSc: I am Johann de Bono from the island of Malta, and I work at the Royal Marsden Hospital in London.

Prof. McVie: So, castration-resistant prostate cancer. It's a new dawn, I would say, as someone outside of the field. Is it a reality? Is it an unmet need?

Hormone Therapy Is Effective, but All Patients Become Refractory

Dr. De Santis: Castration-resistant prostate cancer is common, and patients historically have a very poor survival of only 1-3 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.

Prof. McVie: Does this disease go faster after resistance to hormone therapy develops?

Dr. De Santis: 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 no longer responds to hormone therapy, and develops metastasis and symptoms, mostly from bone metastasis. Patients have bone pain; fractures; and what we call "skeletal-related events," necessitating surgery; and spinal cord compression. So this is serious in terms of the quality of life of these patients, which is not good at all.

Prof. McVie: It's not good, and it's short.

Dr. De Santis: Yes.

Prof. McVie: The biology is changing. Do you have any insight into why -- can you measure it, can you predict it?

Prof. Gschwend: It is all about prostate-specific antigen (PSA) at this stage, because in people who have low PSA levels for a long time on hormonal treatment, even when they have metastatic disease, but at some point in time the tumor becomes castration-resistant; the PSA increases slowly. But afterward, the PSA increases faster, and this is the first problem that is realized by the patient. Later on, the metastasis and pain develop, but PSA is the first sign.

Planning for Castration Resistance at Diagnosis

Prof. McVie: We have nothing better than PSA as a marker; have we neglected the biomarkers, the biology?

Prof. Gschwend: PSA is used the most. It is the best marker we have in prostate cancer. We have some other markers on the horizon, but these markers are more for the diagnosis of prostate cancer, not for the monitoring of prostate cancer.

There is a lot of discussion about the value of PSA in detecting prostate cancer, but this is for locally confined prostate cancer. For the advanced stage, PSA is still the best marker.

Prof. McVie: Now there are hormones.

Prof. Tombal: Hormone therapy was just seen as a treatment for very advanced cancer. As urologists, we try to think more about castration-resistance the day we make the diagnosis, meaning that we are really trying to improve our classification from the beginning; isolate the population of patients who are most at risk for developing castration-resistant disease one day; and trying to implement a multitreatment approach, combining surgery with radiotherapy in these patients. Ten years ago, we were left with hormone therapy alone, but it is very seldom today that you only do castration.

We have basically have had only 2 classes of drugs for the past 30-40 years. We had luteinizing hormone-releasing hormone (LHRH) agonists that mimicked castration, and we had antiandrogens, plus all the other drugs -- general drugs, such as steroids or adrenal inhibitors and angiogenesis inhibitors. Now we have a new class of drug, we have LHRH antagonists that give a new view on the agonist that we use. We are starting to get interesting treatments. Beyond the very new, sexy drugs that are being developed and implemented in very late stage disease, there is a lot of work being done earlier in the disease, to develop new drugs for first-line treatment.

I am convinced that it will be the combination of these 2 approaches: At the beginning and at the end, we are going to move this drug along in the disease, and this is where we are going to see the big improvement.

Prof. McVie: Maria, you showed a slide and asked the audience to vote on 5 options for treating somebody of my age, a 67-year-old man with metastatic castration-resistant prostate cancer. I was amazed that there were 5 options. Johann, this has just crept up on me. We have cytotoxics, we have targeted radiation, we have abiraterone, and other antiandrogens. Where did it all come from?

The Emergence of Treatment Options

Prof. de Bono: It has been really unprecedented in that 2-3 years, we have 5 positive phase 3 trials, when in the 30 years before that, we had 1 positive phase 3 trial for survival that really influenced the field. It has come partly from carefully designed trials that have yielded fruition, but also from an increased understanding of the biology. This is work that dates back to Charles Huggins in the 1940s through Labrie in the 1980s. Jim Mohler did some beautiful work showing that in men who have no testicular function, their prostates were still full of hormones -- really seminal work from Charles Sawyer's group, showing that the androgen receptor remains key to driving this disease.

Now, our work with abiraterone[1] and MDV3100[2] has shown in these big phase 3 trials a survival benefit, confirming that those other studies were correct: This cancer is not hormone-refractory, it is not hormone-resistant, it is not androgen-independent, but truly remains hormone-driven. It is likely that even when these patients progress on abiraterone or MDV3100, the cancer is probably still hormone-receptor driven.

The cabazitaxel trial[3] 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 signaling, particularly impacting tubulin's role in the cytoplasmic-to-nuclear shuttling of the androgen receptor.

The sipuleucel-T work[4] 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. This whole area of immunotherapy is going to be a rich seam for us to mine in the future.

Prof. McVie: The audience answered to your choice of 5 things. First was cytotoxic therapy. You went with that?

Dr. De Santis: Yes.

Prof. McVie: So that is your first choice. Not everybody agreed with you, I have to say. But that is, in your view, the first choice, and that would be docetaxel or cabazitaxel.

Prof. de Bono: That is based on the evidence that we have today. However, we have evidence that such drugs as MBV3100 and abiraterone are highly active prechemotherapy. We currently cannot recommend these drugs for chemotherapy as of yet until the phase 3 trials are completed. On the basis of the cancer biology and the phase 2 trials in this disease before chemotherapy, these drugs are more likely to be even more active prechemotherapy. In fact, like trastuzumab, these drugs may have their most important role in the adjuvant treatment of patients with prostate cancer, and it may improve survival and cure rates in men with earlier-stage high-risk disease.

Prof. McVie: Your phase 3 data were really remarkable, and I was particularly struck going back to your quality of life and bone disease findings in terms of advantage for abiraterone[1]; in this case, the time to skeletal-related events or bony disaster (because that is how it usually goes). So, you can see this drug moving up to an earlier and earlier phase. That seems to be clear. We don't have a HER2/neu and an ERB2 [that can be used as a biomarker]?

Prof. de Bono: We are working on it. There is evidence that these S gene rearrangements are hormone-driven and may actually help us predict the patients who will benefit most. The caveat is that patients who have no rearrangement actually do have some benefit, but we have published evidence in Cancer Research[5] that the patients with these rearrangements are the most likely to benefit. These are genetic chromosomal rearrangements, such as BCR-ABL in chronic myelogenous leukemia, that result in the postoncogene becoming hormone-driven. So, we have some evidence for that and we need to do more work there, and the work is ongoing.

Prof. McVie: I like the way that a lot of your audience also voted for clinical trials, and there is increased enthusiasm and optimism about the oncologists' and the urologists' approach to this whole disease.

In the next bunch of trials, are you going to be looking at head-on cytotoxic abiraterone? Are you going to be looking at combinations -- are you going to be saying, okay, abiraterone clearly has a side effect profile much preferable to docetaxel, so what about the length of the drug, how do you keep on going? You did ask this question, you carry on with this drug out through a year, the PSA is going up, but the patient is sitting fine. What are you doing at the Royal Marsden?

Adjuvant Therapy and a Multidisciplinary Approach

Prof. de Bono: To look at the most important questions, I go back to this issue: Adjuvant therapy with abiraterone is going to be key. If I had to name the one most important trial, that would be it; that is the key trial because I think it will increase cure rates.

Prof. McVie: That is for the urologists, because the medical oncologists often don't get in there yet.

Prof. de Bono: To be fair, we are working in partnership, and I hope that that would be the case and we would move forward, and I would actually recommend that patients see physicians who are working in a team that involves both an oncologist and urologist. Bertrand, I think you would agree with that.

Prof. Tombal: Yes. Unfortunately, across Europe, there are not many countries where multidisciplinarity is practiced. There are some countries where prostate cancer is still treated by a monospecialist. This is the main threat to the development you are now describing.

Prof. McVie: In your country, do you work together with each other?

Prof. Gschwend: Yes.

Prof. McVie: You work together with the laboratory people developing biomarkers, or the imaging people?

Prof. Gschwend: Absolutely. Also, in Germany, we have a strong cooperation among urologists, oncologists, and basic researchers to develop treatment, and mainly in these bigger cancer centers. So I guess that all over Europe, we have several places where we work pretty close together.

Prof. McVie: And Austria?

Dr. De Santis: We are used to working interdisciplinarily and in multidisciplinary teams, and we used to discuss nearly all patients in our tumor boards, where urologists, medical oncologists, radiation oncologists, and pathologists are present. This is a very good forum to discuss patients, and this is really multidisciplinary.

Bone Scans vs PET and MRI

Prof. McVie: I was struck by Anwar Padhani's talk on imaging and defining as well as possible where you go with particular strategies, and also how you define whether you are achieving anything. He was pretty critical of us urologists and oncologists using bone scans now, and he was saying that the time for bone scan is past. Now we are talking about PET for soft tissue and this new diffusion-weighted (DW) MRI, the "cheap and cheerful," quick imaging technique to measure response and progression. Of course, he works with you, Johann, in new drug development.

Prof. de Bono: 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 tumor. Not only that, but if you give drugs that are highly active, such as abiraterone, the bone scan can look worse when there is tumor flare.

Prof. McVie: Unfortunately.

Prof. de Bono: So, to monitor 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. I think what Anwar is trying to say is that for very early stages, if we are 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 would cost probably 50 million euros or more to really prove that these new methods of imaging are actually better than the unproven but established imaging methods.

Prof. McVie: Germany has the money; are you going to do the studies?

Prof. Gschwend: Yes, we do the studies, but not on a large-scale basis. This is the problem. We do all agree that the bone scan is old-fashioned imaging and that it often does not tell the truth. On the other hand, we have the problem that, for example, for PET scanning, we do a lot of PET scanning all over Germany and Europe, but we still do not have any strong evidence that PET imaging is good for prostate cancer for primary diagnosis or for monitoring. And the same is true for MRI. MRI could be done, but it has not been proven that it is really helpful, so this is my criticism.

Prof. de Bono: What we need are regulations that actually control and define how these modalities in imaging become widely utilized as approval mechanisms for imaging. But we need to drive that as the consumers of those imaging tests, in my view. No one has conducted randomized trials to compared CT vs ultrasonography in liver metastasis; it has just never been done. So there is no history or a tradition of randomized trials to develop evidence-based imaging. That has to happen now.

Prof. McVie: What happens in Belgium?

Prof. Tombal: In Belgium, we have a large number of MRIs. Our group already published an article in 2005 in Prostate,[6] which is a good paper for urologists, showing that you can apply the RECIST criteria to bone metastases. Do you know that we went to several companies, and nobody seemed to ask to evaluate this? Everybody is still pleased with using the bone scan inappropriately.

Everybody also mentions the problem of cost, depending on the country. When you see, for instance, whole-body MRI as shown by Dr. Padhani today, it is advertised by many centers not as a way to make a diagnosis, but as a way to make money.

We have to realize that behind modern technology, there is also hype, and we don't know where the limit is of true breakthrough science, because there is always a risk for changing the way you categorize a patient. For example, say you have a very young patient, and you find prostate cancer, quite aggressive. And you think about radiotherapy or hormone therapy; then, suddenly, instead of a bone scan, you do an MRI and you find a 1-cc bone metastasis. Because of that, you say, "No, I am not going to [do radiotherapy]; you will have a prostatectomy."

We need absolutely to find a way to test this, and I think the only way is to go to work with the regulation authorities and force the industry to embed these technologies in the trial.

Prof. de Bono: We need to regulate the utilization of these imaging modalities.

Prof. McVie: I'm sure the time has 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 when the issue of age came up. Now, it is a sensitive issue, but most 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. It is an age bias; in hematology-oncology, we had a meeting in Rome last year, and it was rampant in prostate cancer. It is also a preconceived notion, and we must get rid of that because the kind of studies you are doing show that actually age isn't a factor. It's performance status that's a factor.

Prof. de Bono: First of all, prostate cancer is not a disease of old men, or even older men. There are a lot of men with prostate cancer who are under 65, and this is not that different from breast cancer. But, importantly, age should not influence 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.

A Look Ahead

Prof. McVie: Thank you. Any other last words about what is going to happen in 2013, Bertrand?

Prof. Tombal: I would say no, because nobody could have anticipated in 2003 that we would have the symposium we had today, so I would be very careful about that.

Prof. McVie: Well, that is very careful.

Prof. de Bono: There are some exciting new drugs coming out. Cabozantinib is looking very promising in this disease. The AKT/PI3-kinase inhibitors are looking very exciting. The combination of drugs that we discussed today, such as MDV3100 and abiraterone -- it's an exciting time.

Prof. McVie: And the other immunotherapies, such as ipilimumab.

Prof. de Bono: It's very likely that trial will be positive.

Prof. McVie: Any other last thoughts?

Prof. Gschwend: We have an exciting time in prostate cancer, especially for castration-resistant prostate cancer. We saw this with renal cell cancer 5-6 years ago and now with prostate cancer, and this is exciting.

Prof. McVie: Last word?

Dr. De Santis: 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 waiting for data of the ongoing trials that have finished accrual to have new data and to have hopefully more drugs.

Prof. McVie: So, the bottom line is that we should be putting all prostate cancer patients into clinical trials. Thanks very much for all of your wise words and your enthusiasm, which comes through tremendously. Thank you.

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