New hopes for prostate cancer

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Published: 23 Jun 2011
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Prof Cora Sternberg - San Camillo Forlanini Hospital, Rome, Italy
Prof Cora Sternberg talks about the huge increase in genitourinary oncological research she has seen over her career and the way that research has moved towards a multi-discipline collaborative approach. Apart from notable exceptions such as the development of docetaxel and zoledronic acid there has been very few major advances in castration resistant metastatic prostate cancer until 2010, when abiraterone hormone therapy, the cytotoxin cabazitaxel, the immunotherapeutic sipuleucel-T and the monoclonal antibody denosumab were all approved. Prof Sternberg discusses recent research into a hormonal therapy that improved overall survival in supposedly hormone resistant patients with metastatic castration resistant prostate cancer, explains how circulating tumour cells (CTCs) could be
used as a surrogate marker for overall survival and highlights some key new drugs in development.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).


ASCO 2011 Annual Meeting, June 3-7 2011, Chicago

New hopes for prostate cancer

Professor Cora Sternberg – San Camillo Forlanini Hospital, Rome, Italy


When I first started in genitourinary oncology there were perhaps 5 genitourinary oncologists, medical oncologists, involved in the field.

In North America I expect?

In North America.

The whole lot, yeah, sure.

The field has blossomed considerably since we have drugs such as docetaxel chemotherapy, and medical oncologists have become much more interested and more involved, so there are many more young people involved in genitourinary oncology today.

And are the urologists and the radiation therapists reacting positively to this, or are they resisting?

Well I think that there was initially some resistance; this was a field dominated by urologists and radiation therapists, it still is, but it was really dominated by them. But I think that in this world the multidisciplinary approach has become more and more important in every field. And I think that urologists and radiation therapists are much more likely to collaborate with medical oncologists. For patients with very advanced disease that are castration resistant, in the past we had nothing for those patients, so the urologists really never sent them to medical oncologists; the medical oncologists had nothing to do for them. But this changed dramatically in 2004 with the approval of docetaxel and prednisone so there was now something we could do for these patients, albeit it was chemotherapy. And there is even more excitement now because of all of the new hormonal therapies but I still think that the multidisciplinary collaboration is extremely important. We just wrote a paper with the radiation therapist, Riccardo Valdagni from the European School of Oncology about the Prostate Cancer Unit and how important it is to have multidisciplinary collaboration. And we know that when patients are evaluated with the multidisciplinary approach, very often up to 30% of the time, there are some papers written on this, the approach has changed. So the discussion is helpful for the patients.

So let’s start with the castration resistant metastatic patients, because this has just exploded and you have been a key instigator of the explosion, you said. You didn’t just light the fuse and walk away, you lit the fuse and got stuck in about it all.

I’m lucky, I’ve been involved in it so I’m very happy.

So where are we, 2011 ASCO; we’ve got a lot of drugs, we’ve got a couple through the FDA and are really getting into practice now. Can you tell us a little bit about those, where you think the excitement is?

Well the excitement really started in 2004 with docetaxel. It started in 2002 with zoledronic acid but from then until about last year we have really had nothing, then last year we had an explosion. We had four large positive phase III trials leading to approvals of new drugs, one of the most interesting of which is abiraterone which is a hormone therapy, and we can discuss that further because I find that extremely exciting. One is cabazitaxel which is a novel chemotherapy for patients who have failed docetaxel chemotherapy. One is the sipuleucel-T which is the dendreonic based immunotherapy, and we also have another therapy, a monoclonal antibody called denosumab, which was looked at head to head against zoledronic acid and since this is a disease that primarily affects the bone, having another drug which affects bone and decreases skeletal related events is extremely important.

I’ve been involved in all of these studies. The perhaps most exciting to me recently has been the fact that we understand that although a patient may seem hormone resistant, androgen dependent, we’ve now changed the terminology to castration resistant because it is still possible, although they seem to have castrate levels of testosterone in the blood, that more testosterone can be produced by the prostate cancer cells, by the adrenal cells and therefore, even though a patient has already failed castration by the classical terminology, one or two hormonal lines, they have already failed chemotherapy, we have shown in the paper that was published this week in the New England Journal of Medicine, de Bono is the first author, Howard Scher is the last author, in this paper patients with metastatic castration resistant prostate cancer who had failed all hormone therapy, had failed one line of docetaxel chemotherapy or even two lines of chemotherapy, we could show we could improve the overall survival by more than 4 months in those patients. And this is a big breakthrough; the survival curves are more interesting than anything we’ve seen thus far, with hormonal therapy with very, very few side effects. And this is in the post chemotherapy setting where this has been approved but there is another study that we don’t have the results yet in the pre-chemotherapy setting because obviously, and here the urologists become much more interested. When these studies will be positive in the pre-chemotherapy study setting we will have to re-think what is the right timing for chemotherapy?

Docetaxel is not the nicest of chemotherapy drugs to have turned out be useful in prostate cancer and I suspect a lot of urologists would like to see that going down the line and bringing non-cytotoxics in up front, and let’s hope it works out. I would be surprised if it doesn’t work out frankly. This New England Journal paper is very impressive, it is really impressive because it’s not just the survival data that’s impressive, it is abiraterone plus prednisone versus ...

Versus placebo plus prednisone.

Pain control, time to pain relapse ...

PSA response and what’s going to be presented at this congress is something extremely interesting. The fact is that it’s been very hard to have drugs approved in castration resistant prostate cancer; the majority of our patients, between 80-90% of patients, have bone disease as their major site of disease and these patients don’t have the classical resist criteria that we can look at progression free survival or response rate. So all of the approval strategies have been based on overall survival so it’s been very difficult and we’ve been looking for surrogate end points that will correlate with overall survival. So at this year’s meeting on Monday, Howard Scher will be presenting the first results in a large trial, there are more than 1,000 patients in this trial, in which he’s looking at circulating tumour cells as a surrogate marker for overall survival. And he found that this is a positive surrogate marker. So in the future if the circulating tumour cells are a surrogate marker for overall survival we can conceivably know earlier whether or not patients are responding, we can conceivably study these circulating tumour cells also for genetic abnormalities. We can study them, but we can also have a marker in which we can understand but without waiting until overall survival. And if we have more and more drugs in which there will be crossover, and it’s more and more confusing to have the overall survival difference, it would be nice to have a marker early on and so this is a very important paper. The CTCs are being incorporated into all of the on-going studies and there are many other on-going studies at this time, aside from the abiraterone study, in the pre- and post-chemotherapy setting with other novel hormonal agents.

As a point of interest, do the CTCs change when you put patients on denosumab?

I don’t believe that they were measured on the denosumab. It’s a very good question.

It’s a completely different mechanism of action, it’s a bone related drug.

It’s a different mechanism. It’s a monoclonal antibody against RANK ligand, and zoledronic acid was approved after being evaluated in 2002 against placebo, and it’s been the standard of care for castration resistant prostate cancer. The denosumab study was initially designed as a non-inferiority study, there were 1900 patients and it was compared to zoledronic acid, and was found to be actually superior showing an 18% reduction in the risk of the first and second skeletal related events and I don’t believe that the CTCs were incorporated in that study but I’m not 100% sure.

It was just a point of interest, because there’s still some mystery as to the mechanism of action, the mechanism of anti-cancer action of this interesting antibody. Now, you lectured at the European Institute of Oncology in Milan a couple of weeks ago and it was a sparkling lecture.

Thank you.

At 7.30 in the morning ...

Thank you.

And you listed another eight drugs that are coming down the pipeline, presumably why we need to the CTCs as an intermediate biomarker, because we have got, for the first time, not just a couple of active drugs, and very active drugs, but we have actually got a waiting list.

We have a waiting list. The abiraterone works by blocking testosterone production so it blocks... testosterone is the ligand which attaches to the androgen receptor, so we block the ligand. But the other drug that is very far along is called MDV3100 in a very similar setting being tested in a post-docetaxel setting and in another study it’s called AFFIRM, and in another study called PREVAIL in the pre-docetaxel setting. And this drug actually has three mechanism of actions, not just blocking ligand production but also blocks incorporation into the nucleus and in DNA binding. So it can also theoretically work on the androgen receptor that has splice variants and changes and doesn’t have the ligand receptor. So it theoretically has a different mechanism of action, and that’s the MDV3100. In our institute we’re working with another drug called TAC700; it’s somewhat similar to the abiraterone. Once again we have studies going on in a post-docetaxel setting and a pre-docetaxel setting but it is becoming, and it will become, more and more difficult to do the kind of studies that we’ve done. The abiraterone study was done in the post-docetaxel study with a 2:1 randomisation against placebo, but as we have these active drugs we won’t be able to use placebo anymore, we are going to feel an ethical obligation to give these drugs to our patients. So we will have to change our landscape in the way that we conduct our studies.

And I would bet that the pre-chemo trials are going to come out positive.

The pre-chemo trials are going to be more complicated because at the moment they are still looking at overall survival.

Which is a long way down the road.

It is a long way down the road, so that’s why most of the registration trials have gone for the post chemotherapy.

Sure.

I am working with another drug called tasquinimod which has a completely different mechanism of action. It has been studied by the John Hopkins group, it’s primarily anti-androgenic, also in the pre-chemotherapy space it’s also very exciting like a number of drugs.

And presumably the CTCs would possibly have a role to play there too?

Yes, I think that CTCs could be very interesting.

You expect that these new drugs are going to avoid the long-term consequences that were seen with the previous androgens, and we are now faced with the late effects of androgen manipulation in prostate cancer patients who are living longer and they are getting heart disease and lots of other things.

I think that that’s a wonderful question and I am afraid what the answer might be because we know that suppression of the hormonal testosterone access for men on the long term is a problem in terms of cardiovascular morbidity, cholesterol, hypertension, there are changes in the subcutaneous fat; the men are different, osteoporosis. And we don’t know what happens when we further suppress this androgen access for longer amounts of time, it may be that these patients have more effects. They live longer but they may have more effect, we don’t know. We need more long term follow up; that’s extremely important.

So ASCO 2012, Cora, what’s going to be the headline?

What is going to be the headline ASCO 2010, that’s a great question. I think in prostate cancer we will have the data on the pre-chemotherapy I hope, the abiraterone. We will have the data of the AFFIRM study which is the MDC3100 post-chemotherapy. I don’t know if the other studies will be ready by then.

OK, promise me you will talk to us in a year’s time.

Whenever you want, it’s a pleasure for me to talk to you, thank you very much.

Thank you, Cora.