Phase III trial of an alpha-pharmaceutical

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Published: 24 Sep 2011
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Dr Chris Parker - The Royal Marsden Cancer Centre, London, UK

During a press conference at EMCC 2011 in Stockhol, Dr Parker gave a presentation on the first Phase III trial of an alpha-pharmaceutical shows improved survival in patients with bone metastases and advanced prostate cancer

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

Phase III trial of an alpha-pharmaceutical

Dr Chris Parker – The Royal Marsden Cancer Centre, London, UK



Thank you very much. I’m presenting the results of a large trial of a new drug for prostate cancer called radium-223. The trial was conducted in more than 150 hospitals throughout 19 countries, so I’m presenting it on their behalf.

If you can cast your mind back to your school chemistry lessons you will remember that radium is very similar to calcium, they’re in the same group of the periodic table. It’s that similarity which leads targeting of radium to bone metastases because if you have an injection of calcium in the blood stream, it goes to the skeleton, it goes to the bones, and it particularly goes to areas of new bone formation such as metastases from cancer. The body handles radium precisely the same, so an injection of radium goes to bone metastases. But unlike calcium, radium is an alpha emitter and alpha particles are highly damaging, very lethal but they’re also very, very short range. So the rationale is, the theory is, that if you’ve got radium in your bone mineral then any adjacent cells, any adjacent cancer cells, will be killed by the alpha particles but the more distant bone marrow cells are spared and that’s what this cartoon is meant to indicate. So you’ve got radium sitting in the bone mineral structure, cells very, very close to it are killed by the highly lethal alpha particles but more distant cells and the normal bone marrow are spared, so that’s the theory.

This is the trial, it was called the ALSYMPCA trial, which involved over 900 men all of whom had advanced prostate cancer with bone metastases. They were randomly allocated either to receive radium or placebo in addition to best standard care. So they all received standard care for men with advanced prostate cancer and bone metastases and, in addition, they received six injections, one injection every four weeks, of either radium or placebo. It was a double blind trial so the patients didn’t know, the doctors didn’t know which they were getting.

Here’s the main result, so the main endpoint of the trial was overall survival and treatment with radium was associated with a significant improvement in overall survival. A hazard ratio of 0.695 translates into an advantage of 30% in overall survival.

This is the first drug that is targeted to bone metastases in prostate cancer to improve survival. So there other bone targeted drugs that are used in prostate cancer but they help to minimise symptoms, they don’t improve survival. So this is an important result.

The other side of the coin is the safety and radium-223 was extremely well tolerated. One looks at the hematologic side effects because one is concerned about the possibility of bone marrow problems but if you look at significant toxicity, so grade 3 or 4 toxicity, you can see that there is an effect. So in the placebo arm we’ve got 1-2% significant hematologic toxicity and in the radium arm we’ve got 2-4%. So there is an effect but it’s pretty rare. The only other side effect that is apparent from the trial is that there is an increased risk of mild diarrhoea and mild vomiting but there is no difference in severe GI symptoms. So, on the whole, the drug was extremely well tolerated.

So, in summary, in men with advanced prostate cancer and bone metastases, radium-223 prolonged survival. I didn’t show you the data, but it also prolongs the time to skeletal related events. So when you’ve got bone metastases from prostate cancer you’re at risk of developing fractures, you’re at risk of developing spinal cord compression, other complications, and those complications were delayed by treatment with radium. Then thirdly, it was extremely well tolerated. So, in my opinion, radium-223, subject to regulatory approval, is likely to become a new standard treatment for men with advanced prostate cancer and bone metastases.

Thank you.

Chairman:
Thank you very much. Now we’re going to take questions, so if someone wants to raise the first question, the gentlemen and then you… Go ahead. With the microphone, if you can identify yourself.

Questioner:
Yes, Pieter Droppert, Biotech Strategy Blog. This is for Dr Parker, a couple of quick questions for you. Could you just clarify where this… you said in the statement then, new standard of care, where does this compare to, obviously, denosumab in its skeletal related events? I don’t have the data in front of me. And do you have any data to show its effect on pain and quality of life? Because I know when the cabozantinib data was presented that was discussed as a proxy for overall survival although they didn’t have that, I’d be interested to know where that fits in. My second question is where does this fit into the scheme of life in the post-docetaxel setting when you have obviously androgen receptor antagonists such as abiraterone recently proved? Will this be an alternative to that or will this be something that will be in combination?

Dr Parker:
That sounds like three questions to me. The first question was with regards to denosumab and skeletal related events. So when I talked about the fact that we already have bone targeted therapies I was thinking of denosumab, I was thinking of zoledronate, but so far those bone targeted therapies have only been shown to help with symptom control in delaying skeletal related events. They have not been shown to have any effect on survival, so I think this marks out radium-223 as very different and a significant step forward.

The second question was about quality of life. So pain was not studied as part of the ALSYMPCA trial, so we don’t have pain data from this trial; we do have pain data from a phase II study of radium-223 and it is an effective method of pain relief. Quality of life was measured in the ALSYMPCA trial but the data are not yet available, so they’ll be presented at a later date.

And then the third question about abiraterone and other new drugs coming along, well it’s not at all clear at the moment where radium-223 will fit in in relation to all the other drugs. If I could speculate about the long-term future, I would say the combination of treatment with abiraterone and radium-223 looks very attractive. You’ve got two drugs, both of which prolong survival, both of which are extremely well tolerated, which work in completely different ways. So, to me, it’s logical to think about the possibility of combining them.

Chairman:
So we have another question. Do you want to ask the same question or are you done? So in the back then?

Questioner:
I’m Charles Bankhead with MedPage Today. This question also is for Dr Parker. Radiation therapy has been used for a long time in the treatment of bone disease and in prostate cancer. What rationale did you have to think that this particular agent would do better than the radiation that’s been used in the past?

Dr Parker:
I guess one aspect of radium-223, which is completely novel and is unlike any previous treatment tested in prostate cancer, is that it’s an alpha emitter and alpha radiation, as I mentioned, is extremely damaging. So a cancer cell only needs to be hit by one or two or three alpha particles to be killed whereas if you talk about beta radiation, for example, that requires thousands of hits to be killed. Furthermore, the alpha particles are very short range whereas other types of radiation, like beta radiation, are long range. One of the limitations of beta radiation treatment was the toxicity to the bone marrow. So those were the two theoretical reasons for thinking that radium-223 might be more effective than beta emitters and the data shows that it is.

Panel Member:
Did you also ask whether compared to external beam radiotherapy, because this is a systemic approach which is completely different because it can work in much more progressed bone metastasis, compared to external beam radiation.

Dr Parker:
Yes, thank you for that.

Questioner:
Susan Mayo from the BMJ, also a question for Dr Parker. A fairly simple question really, how straightforward is it for hospitals to store and use radium-223 for patient treatment? So, thinking if it gets into more routine use, where would it be stored and how is it administered and under what conditions?

Dr Parker:
It’s a very simple treatment. It takes five minutes to administer by an intravenous injection. It’s an outpatient treatment, the patient is free to leave the hospital straight afterwards. The storage is extremely straightforward, again because of the very, very short range of alpha radiation. Alpha radiation is stopped by a sheet of paper, so it’s certainly stopped by a vial. So you don’t need any lead lined boxes or anything like that, so the storage is very straightforward.

It wouldn’t be stored for any great length of time, so it’s manufactured and then would be administered within two weeks of manufacture because it decays with a half-life of eleven days. So the drug would be manufactured, shipped to the hospital and used within two weeks.

Panel Member:
One additional comment to that, I agree completely with Dr Parker that this is a very easy to handle drug in a hospital but radiation protection laws are national in Europe and, in some countries, even regional. So that will of course, complicate the fact to introduce it all over Europe, or at least it may prolong it.