ASCO GU 2013

ASCO GU: Update on clinical study results presented in mCRPC

Professor Eleni Efstathiou – MD Anderson Cancer Center, USA

What is the latest news from the COU-AA-302 study?

This is a significant update on the analysis that we were presented with last year in ASCO and was recently published in The New England Journal of Medicine. This was a planned analysis, the third in a row, and we were anticipating to see the results. The results confirm those that led to what is now the approval of abiraterone acetate in the chemo-naïve castration resistant setting and this has occurred, as you know very well, both by the FDA and the EMA, so on both sides of the Atlantic. What is important with this new data that was presented is that we can not only confirm that there is an increased radiographic progression-free survival, we also saw that the overall survival difference is there but is not significant as we wanted because, I would advocate, we had to unblind the study early as was commended by the independent review committee and was ethically acceptable. What was also important about this presentation was that we found no new safety concerns with this more prolonged administration of the drug. Having said that, I would advocate that now we have more robust evidence of a reagent in the androgen signalling area that helps prolong survival and improve quality of life.

What do you think clinicians should be taking away from this data?

We cannot rush into use because that would probably implicate using it too early. What we can say is that there is a clear indication for those patients who have metastatic disease that is castration resistant, that these patients can and should, in my opinion, receive a drug, abiraterone acetate, in combination with prednisone and in combination, of course, with LHRH treatment.

Can you tell us more about the READY trial?

This was a trial that we started off a few years back, I would think it’s almost five years. Very interesting trial in the sense that we’re trying to combine a cytotoxic chemotherapy, docetaxel, with a Src inhibitor that has been approved in another disease setting, a drug that inhibits osteoclast activity and we would anticipate it had some information that it works in the bone microenvironment, exactly where prostate cancer cells like to home when metastatic. However, we have yet another trial, I am sorry to say, that has been negative and this is in a series of such trials, probably the eighth or the ninth if you actually include the VENICE trial that was also presented today, and it is completely negative.

Can you tell us more about the VENICE trial?

Aflibercept is a also a drug that has shown activity in other disease settings and we were hoping, it was very hopeful to give us positive results in metastatic castrate resistant prostate cancer. Unfortunately, this study was also negative.

Can you tell us more about the combination therapy of Enzalutamide and Abiraterone?

We have actually initiated such a trial after the results that we got from first providing abiraterone to patients, providing enzalutamide and we came up with the rationale that the combination might augment the activity of androgen signalling inhibition in those patients. This trial is currently accruing rapidly and we hope that this time next year we will have some very exciting results with regard to the teaming of these two reagents.

Tell us more about the markers on this study?

Fortunately I would advocate that the failure of these studies, such as VENICE and READY, have to do with a lack of us looking for specific predictive markers and actually identifying that subgroup of patients that are meant to actually respond to these reagents. And the future lies in that exact part of therapy development, i.e. identifying predictors of outcome, positive outcome, and also resistance to a new drug. I think that is essential, crucial and integral to the development ahead of us.

What is coming next in clinical research?

There are several institutions collaborating right now at providing this option research-wise, looking into whole exome sequencing, trying to identify such predictors. These are huge undertakings, these are still in the research realm, not to be applied to clinical practice. But I truly believe, I’m very optimistic, since we’re having such drug development that very soon this research and identification of the prostate cancer biology will pair up with the drug development and lead to the improvement of lives of patients.

Are you excited by the new improvements in mCRPC?

I think that we have made such wonderful improvements in these past few years, just three years, coming from only one drug in castration resistance, to five new reagents with different mechanisms of action and we are all extremely enthusiastic which makes me a little bit more cautious, feeling that we may miss out on opportunities because all these drugs have shown improvement in the quality and overall survival of these patients and they need to be prioritised in the right order if we’re going to truly help patients.

How would you advise clinicians to use these improvements in clinical practice?

For the time being, in general medical practice, there are clear guidelines with regard to what to do when you’re treating a patient who is hormone sensitive. You should use the standard approach of castration, medical castration or surgical castration, if it needs to be continuous that can be a choice, or intermittent, given the current guidelines in earlier biochemical recurrence disease. In the castrate resistant metastatic disease, there is a clear indication for the use of abiraterone acetate, an androgen biosynthesis inhibitor, hopefully we will have more in the future. The problem arises as to the decision as to when to use a reagent that is a chemotherapeutic such as docetaxel. That has not been clarified and I believe there are some clear clinical parameters that guide the use in our practice. For instance, when you evaluate a patient we can tell if he’s clinically progressing, rapidly becoming symptomatic, having other signs of progression of his disease and in that case I would strongly still consider a chemotherapeutic agent, namely, for the time being, docetaxel. The rest of the agents are still the two approved cabazitaxel and enzalutamide are following chemotherapy with docetaxel. So I think at this moment we have some clear paths in our clinic, in a year from now this problem, which is a good problem to have all these drugs, is going to augment and we’re going to be here trying to have found some predictors of outcome to use and implement.

What is your take home message for the clinician?

The disease remains, to an extent, androgen dependent though castrate resistant, always keep that in mind. We’re talking about what we call the bulk of prostate cancer cases, there are exceptions of course. Moreover, there is a clear tumour microenvironment dependence before the disease takes off and becomes very aggressive and then needs to be treated with chemotherapy. With that in mind we have a lot of opportunities to now treat the patients with new reagents that are targeting androgen signalling before moving on to a chemotherapeutic reagent.