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

Care of patients with advanced prostate cancer

Dr Eleni Efstathiou – MD Anderson Cancer Center, Texas USA and University of Athens, Greece

Has the last two or three years changed standards of practice in multi-disciplinary care of advanced prostate cancer, or not yet?

As you said, I have been very fortunate to actually be part of this transition. Back in 2004, when I finished my first fellowship in medical oncology, everyone was more or less wondering why I wanted to go into prostate cancer since, as you mentioned, it was only docetaxel coming through and we had given up hope on a lot of different therapeutics progressing in the field. Well it seems that it actually is a disease that’s the most common in males; it needed a lot of research and effort put into it and a fresh view on how to approach it. Moving a little bit away from the chemotherapeutic view of life but actually applying the same paradigms that we have been applying to solid tumour therapy, meaning that whatever we’ve seen work in the far advanced disease maybe we’ll need to move it on in the earlier disease setting. Having said that, we just needed to go back to the ‘40s and an urologist, Huggins, and actually he never applied and said that that was dogmatic, that if you actually oblate the gonads and the adrenals you’re done. I think he had left an open door there, suggesting that there was further advancement to be made.

Interesting historically that it was a Scottish surgeon, again, who invented hormone therapy in breast cancer by castrating cows and a sheep, that’s by the by.

Absolutely.

So you got interested and you got involved and you’ve been doing translational research in Texas.

So this is exactly what’s been happening in the past five to ten years, maybe, preclinically with Dr Geller and then other scientists involved in the preclinical field looking into what is the adaptive response of androgen signalling following castration. And we have a robust body of evidence, even before going into the clinical application that we’ve seen recently with all these new reagents in the clinic, that there was evidence of altered androgen signalling in the tumour microenvironment that needed to be targeted. That led to the wonderful timing of androgen biosynthesis inhibitors coming in to play in the clinic and novel antiandrogens, as we see now, and other pathways that possibly interact with androgen signalling being tested in the clinic. Going back to your initial question, whether these two or three years of such rapid clinical development have, in fact, made a change, well I think we’re now into such a mode of drug development that we need to sit back and look at therapy development, essentially. How are we going to apply them in the clinic, what is the sequence, what is the combination? Are we going into new foundational therapies or not? And it needs a lot of care into finding the actual predictors of outcome that will guide this successful application.

But let’s just tell me if management of advanced prostate cancer is the same in MD Anderson as it is in Athens, and if so, what is it?

Well that it is. I have to say that in general we have looked in Europe, and you probably have more information where you’re situated strategically, with regard to whether chemotherapy is indeed applied in the far advanced disease state. It seems that there’s a range from 40% to 60% of application of chemotherapy, given the limitation of other comorbidities, the patient not really wanting to have chemotherapy. So I would say that exists across the Atlantic but I believe that the same principles of good clinical practice are being applied, it’s just that Texas, MD Anderson, would be more research oriented, thus giving the opportunity to a lot of those patients to get into clinical trials and participate in those, giving them quicker the experience of the novel reagents.

So have you now changed your standard practice in MD Anderson? Have you brought the new drugs into play? Standard routine outside clinical trials.

Absolutely.

And what is it? Tell me how you do it, what’s your regimen?

As you know, abiraterone acetate has been just about over four weeks approved, so it’s just starting to be used.

In the FDA.

FDA approved, not EMEA. We have access in Europe as well, through an expanded access programme, but that makes it a little bit difficult to get your hands on the reagent quicker.

It’s tough that it’s a UK drug, however, coming back to that again. It’s part of my history.

Absolutely, and a wonderful idea, sitting on a shelf for quite a long time.

That’s an embarrassment, don’t go into that. So abiraterone is in and it’s in standard…

It’s in and it is in standard.

First line?

Not yet, we wouldn’t say that. The approval is chemo treated; we’re waiting on the 302, the chemo naïve trial, to see and it’s very challenging to hold back. We anticipate that we will move.

But we’re evidence based and we don’t do that yet. What about these patients that you were referring to in both Athens and Texas who don’t want chemotherapy, they get nothing still?

Well you’re referring to those who can’t get expanded access.

They’ve got comorbidity and so on, they don’t qualify for getting docetaxel, or else they refuse it.

Or they’re asymptomatic and they don’t think it’s yet time to get docetaxel.

Yes, exactly.

Those patients have the opportunity to participate in other phase III on-going trials where it’s ethically correct to actually treat on a placebo based control and we use other hormonal manipulations that we’ve all been accustomed to if the patient history and all the clinical parameters fit the phenotype of somebody who is still androgen addicted. Then you have those type of patients that seem to be exploding and have more of an anaplastic type of disease, with visceral mets, with a large burden of disease but low PSA, then you would try probably to convince the patient that it’s time to get chemotherapy. Because I truly believe this is a subset of patients where the chemotherapy…

Do you need a re-biopsy for that? I’ve been hearing about circulating tumour cells and so on as a surrogate.

 This is a very important part of my research. It is important and essential to ensure the comfort of the patient, we all say that. We believe that given the predisposition of the disease to go to the bone marrow, a bone marrow biopsy sampling will actually be very informative. We do not have concise evidence yet to move forward with that type of approach but we can indeed, within the context of a clinical trial, include that type of approach and that’s where we’re at right now.

So we’re over the moon about abiraterone, that’s just a terrific step forward, no question about that. But that’s not the whole story, is it? What else is going on there and is there anything here at this ASCO meeting which you’re saying “Ah!”?

We’re actually waiting today to hear more things about abiraterone, of course, again and some other new reagents like XL184, we’re going to hear some interesting data; this is in another exciting pathway that’s being targeted right now. Then we have the advent of the novel antiandrogens with MDV3100 being more advanced in the field, waiting for phase III trial results. And we’ve had experience with a phase II trial that we’ve been conducting at MD Anderson; it’s more of a translational research oriented trial but we’ve had similar outcomes with regard, at least, to PSA declines, and some very convincing clinical responses in the initial phase of this study. And of course the prior experience in the phase I, II suggests that there’s room for androgen receptor blockade that will be meaningful in the disease as well. So, with regard to other pathways, we won’t here a lot during this meeting because I think a lot of the other pathways that are being targeted are in the phase III setting right now. So we’re all anticipating some analysis on-going, such as the Src pathway and other pathways targeted by lenalidomide, let’s say, and other drugs of interest.

So ASCO 2012, what are you waiting for?

To actually see if the androgen receptor blockade in fact works in a similar manner as anticipated, based on these results. And to get that adaptive response of androgen signalling within its interaction with other pathways, whether we can actually target it and get even better results towards therapy application. More importantly, I hope to see more of the translational research that is needed to actually figure out how to prioritise treatment or combine treatment.

And trials which will be mature by then, that you’re waiting for?

The MDV3100 phase III in the chemo treated, I anticipate; the combination of docetaxel with dasatinib, the Src inhibitor. I think these will be two that should be mature by that time and then there’s a few other radiopharmaceuticals on-going, like alpharadin that we’re waiting on some interim analysis data.

With abiraterone up front?

302, maybe sooner.

Will that be coming up by then?

Maybe sooner, definitely by then. I would anticipate it sooner.