Professor Ryan, Charles Ryan, from UCSF, thank you very much for coming all the way to Madrid and for taking time out to talk to ecancer. You’re giving a plenary lecture about the new horizons in management of prostate cancer and it’s really quite exciting. Now, you’re a Professor of Medicine and Urology?

That’s correct.

So looking from San Francisco, what’s your view of prostate cancer management? It’s changed quite dramatically just in four or five years.

Absolutely. First of all it’s a pleasure to be here in Madrid, always, and to be presenting new data which is interesting and exciting. The management of metastatic castration resistant prostate cancer has undergone a sea change in the last five years. We have five new agents that are available that have received regulatory approval because they have improved overall survival for patients. So what that means is, of course, survival has never been better but we now are seeing sequential use of more than one of these therapies. So that is, on the one hand, very exciting and important for us in the clinic; for those of us who design and implement clinical trials it creates a few issues in terms of designing trials that can incorporate the potential or the possibility that patients will receive numerous therapies sequentially.

Just to be quite clear, these five new agents have been OKed by the FDA for treatment of castrate resistant prostate cancer after chemotherapy?

A mixture.

So what would that all look like?

Going back ten years we had docetaxel chemotherapy then we had cabazitaxel, which is a taxane chemotherapy approved for post-docetaxel patients. Then in the US we had sipuleucel-T, a cellular vaccine approved that was irrespective of chemotherapy, really. Then we had abiraterone approved in the post-chemotherapy space, then in the pre-chemotherapy space. Then we had enzalutamide approved in the post-chemotherapy space and, very recently, at least in the US within the last couple of weeks, it was approved in the pre-chemotherapy space as well. Add to that radium-223, I forgot about the other one.

With the bone seeking isotope? And none of these agents are tested in the non-metastatic situation yet.

Tested, yes, validated, proven and approved, no. Still early on.

How many years for that?

A long time probably. The reality is with prostate cancer is that men who undergo treatment with curative intent, be it surgery or radiation, who then develop progression after that treatment and then go on to have a life-threatening form of the disease, that natural history plays out on the order of somewhere between six and fifteen years. So early stage studies, although they are very, very important, they require a large sample size and a long follow-up. Fortunately we have some of these studies that are underway, adjuvant chemotherapy studies, that type of thing, but they’re just in the period of time where we are in follow-up mode or data collection mode and we don’t have the answers.

But at ASCO this year we did get a nice phase III trial using cytotoxics plus androgen deprivation therapy. That’s going to change things a little bit in terms of the multidisciplinary -

Absolutely. Now, keep in mind that’s not really an early stage patient population. That is an untreated metastatic group of patients so the metastatic castration resistant group is late stage disease, if you will, where the expected survival is in the order of about four years. With the untreated metastatic disease those are patients who still have hormonal therapy available to them, they are not resistant to the hormonal therapy, so it’s a slightly different patient population.

And you’re giving us the last update and really the final results of this really important trial which has to be important because you’ve come all the way from San Francisco to tell us.

Well I would have gone anywhere to present it. This is the final analysis of a phase III randomised trial. It’s the COU-302 study, we call it the 302 study. The importance of this study is, number one, that the patients in this state of the disease, these are patients who are asymptomatic or minimally symptomatic, they’ve not received prior chemotherapy, and the goals of therapy for these patients are to preserve an asymptomatic state, prevent complications from the disease, delay progression of the disease and, of course, improve survival. In previous analyses we have shown very robust data demonstrating a delay in radiographic progression that’s highly statistically significant. We showed a very strong trend in favour of survival for abiraterone compared to the prednisone control. But the final analysis that we’ve presented here now shows that with 96% of the deaths having occurred we see a statistically significant improvement in survival and this has occurred despite a series of interim analyses. So it wasn’t always apparent that this was going to be present. It demonstrates a couple of things: one is that therapy improves survival definitively, statistically significant, no problem there. But it also demonstrates the power of completing a trial. The study was unblinded two years ago but the study was not terminated, actually two and a half years ago, and completing the study to its final conclusion is really important because we have new data now.

And you got crossover data too?

We got crossover data. There were 9% of patients who formally crossed over per protocol, however, in reality 44% of the patients initially allocated to the placebo arm have received treatment with abiraterone. These make the data even more impressive, that 44% crossed over to the actual study being tested. There was a huge amount of crossover, if you will, to other active therapies, so these five other treatments that have been demonstrated to improve survival, many patients got more than one of those.

But you can analyse this according to the intention to treat? And also you’re developing a new strategic vision; this is the strategy for the future that you’re now saying, OK, you’ve got castration resistant patients with prostate cancer, they’ve got hopefully not any problems with their disease or they may have minimal problems, and then you’re saying the standard of care is now…

The standard of care for many patients is abiraterone in this setting. Again, getting back to my previous point, this is a study and a therapy, the use of this therapy in this group of patients preserves quality of life, preserves the good performance status, prevents the complications etc. I think that’s really an important point and it’s different, for example, from treating, not to diminish the importance, but patients who have very advanced disease who are symptomatic. We, of course, want to alleviate those symptoms but we would like to prevent or delay them if we could in the patients who don’t have them yet.

So this has become standard of care in the United States or on the way?

In the current era, yes, it is one of the standard treatments for patients who are chemotherapy naïve. It’s widely utilised and, of course, is now the foundation for combination strategies etc.

And will those be combinations or will they be sequential use of the other active agents?

That’s the big question in the field. Nobody has demonstrated in prostate cancer really the benefit of a combination strategy. However, most of the combinations that have been tested have been a drug with a survival benefit and another drug that doesn’t have a proven survival benefit so now we need to combine some of these five or six agents, see how that works. We need to further clarify who are the patients who benefit from this approach versus not, we need biomarkers to help us do that and that field is progressing as well.

I’m delighted that you’re bringing the drug back to Europe where it started. Congratulations.

Thank you very much.

We wish you well with the combination studies because that could make things even better.

Absolutely, let’s hope so. Thank you very much.

Thanks, Charles. Thank you.