European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Radium-223 in castration resistant prostate cancer

Dr Joaquim Bellumunt – Hospital del Mar, Barcelona, Spain


Professor Bellumunt, thank you very much indeed for coming all the way from Barcelona with… I don’t think there can be any doctors left in Barcelona, at this ECCO meeting.

No, probably not many.

You are doing a lot things here, you’re presenting some really top class and some breaking news. You’re embargoed for two hours, we’ll not be going out until then, tell us about it.

We have these late breaking abstracts regarding prostate cancer, castration resistant prostate cancer. We are going to hear the results of alpharadin that is a new radioisotope, in fact it’s radium-223 and is an alpha emitter and is completely different from the beta emitters because we remember that in the years when we were using samarium…

Strontium.

Strontium, those were gamma emitters or beta emitters.

And very myelosuppressive.

A lot of myelosuppression, so this was the last shot that could be given to the patient because after that, the myelosuppression did not allow to give chemotherapy and nothing else. With alpharadin, one of the good things, in addition to providing survival benefits, is that this treatment is being given every four weeks for six times and it does not produce myelosuppression so the side effects are minimal. And it seems, because while this needs to be prospectively validated, patients can receive subsequent therapy. The fact is that in this trial it has been done in patients having castration resistant prostate cancer but there are 40% of those patients who were not eligible to receive docetaxel. So it’s a mixed patient population.

And it works after docetaxel and it works without docetaxel?

Yes. Well the population, being unfit is not well defined in the presentation, probably it’s going to be better defined in the future. 60% of patients did receive prior docetaxel and 40% did not receive because of being unfit for docetaxel. Now what they have said is that probably this patient population being unfit are elderly patient populations with poor prognostic factors and probably the survival is more or less the same as those patients who are fit for receiving docetaxel. And they have seen a survival advantage in both groups of patients so it doesn’t matter if the patient has received prior docetaxel or not, being unfit.

So that’s good news?

Those are good news. So in fact the setting or the indication is going to be after docetaxel overall but in this patient population this is a good thing to be used because we know that presently close to 40-50% of patients are not suitable to receive chemotherapy because of age, comorbidities or something else, so alpharadin could be a good option. The other point that needs to be studied if it is suitable to be used with chemotherapy and probably more studies need to be done if chemotherapy can be given to these patients. There is no data about cabazitaxel use in these patients so we do not know if there is going to be an increase in myelosuppression. We know that cabazitaxel that is approved in second line in patients failing docetaxel produces 83-84% of grade 3 neutropenia that finally is irrelevant and can be managed with growth factors. So the way we are going to integrate all these treatments is very important. The good thing for the patient is now we have a lot of options, we have abiraterone…

Five years ago we had nothing.

Nothing.

So abiraterone, let’s get the pronunciation right.

Abiraterone, yes we have to learn abiraterone, cabazitaxel, all these new names. So since 2004 when we heard about the results of docetaxel, we have been waiting for six years until 2010 we heard about abiraterone, we heard about cabazitaxel, we heard about denosumab that even though it’s not improving survival it’s delaying skeletal related events and we are going to hear that denosumab is able to delay the appearance of metastatic disease, bone mets, in patients with CRPC having no mets at the time of being included in the trial. So this is going to be presented by Stephane Oudard and Stephane Oudard is going to present the subgroup analysis because this was already presented by Matthew Smith during AUA. So it’s going to be an update of the results so the information is there. There is a four month delay on the appearance of bone mets. So we’re having newer options in CRPC so we have heard about cabazitaxel, abiraterone, denosumab, alpharadin and more drugs to come.

So you’ve got a patient with castration resistant prostate cancer, which order are you going to test these new gifts that have come from the research labs?

Yes, this is the one million question. Presently, unfortunately, we do not have exact ways to decide what is the best to be given to the patient so still our decisions need to be based on clinical assumptions. We know that the toxicity profile when comparing abiraterone and cabazitaxel is completely different. The setting or the indication for both agents is more or less the same, it’s after docetaxel. Abiraterone was even tested in patients who did receive docetaxel and mitoxantrone, so even a worse patient population. Finally, both produced survival benefit. We cannot compare one trial with the other but unfortunately we do not have predictive factors of response when using abiraterone or cabazitaxel. There are assumptions, so maybe patients with a short PSA doubling time are going to benefit most from receiving chemotherapy but in fact there are patients with, for example, visceral disease like liver mets, who are responding to abiraterone that initially people were believing that probably patients having visceral metastases were not going to.

Any chance of a head to head comparison?

This is not going to be done.

Because the pharma won’t do it?

Initially because pharma is not interested and probably what we need to do is to learn how to sequence these agents and we need to learn and now some retrospective analysis of the database is going to be done. I’m going to just go back to what was published by Armstrong in 2010, number/grams predicting the outcome in patients who receive docetaxel. Not only pre-therapy factors but there is a recently published number/gram in Clinical Cancer Research where the response to docetaxel is taken into account. So post-treatment factors have been integrated in this number/gram and maybe what abiraterone, cabazitaxel patients we need to do is just to go back and see, based on these predictive factors of response or prognostic factors, we don’t know what is the outcome of this situation. So a patient having, for example, received less than the ten cycles of docetaxel are doing worse; patients who do not respond initially, patients having progression pain, bone or vesicle disease, depending if you have one, two or three, the outcome is worse when receiving chemotherapy.

You desperately need some biomarkers here and one of the problems with prostate research is that there’s not enough of it. The amount of translational research being done on prostate cancer, compared to breast cancer, is logs different. Are you optimistic that something is going to come out of the translational research labs on prostate that will help you with this?

Yes, for sure. In the future we are going to characterise patients on this. A CRPC patient is in this group because he’s having alternative splicing of androgen receptor or he’s having the translocation, the TMPRSS2-ERG and this has been shown to be predictive of abiraterone response. This is the only potential predictive marker. Or maybe CTCs are going to be useful to decide which patient is going to derive benefit when receiving abiraterone early and we do not need to wait for the PSA or do bone scans and so on. So hopefully we are going to know more and more.

We’ll get an answer. For the moment if it’s your father with prostate cancer, castration resistant, are you going to say abiraterone first, given the side effect patterns?

I would like to give it even before docetaxel. So I think this is the future. Nowadays we still do not have the results of the 302 trial but hopefully it’s going to be...well its really well-tolerated. In the randomised trial you were not able just to decide if the patient was in the placebo or on the drug based on side effects, you discovered the patient was receiving the drug because the PSA went down pretty soon.

I think this is an exciting area indeed. The next ECCO I think, a lot of these answers will be in two years’ time.

Hopefully.

Maybe something next year at ASCO but I think it will take a little bit longer as you suggest. Thank you very much again, Joaquim, I really appreciate speaking with you.

A pleasure.