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From: tnsaf10/30/2011 11:46:41 PM
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Dr. Chris Parker: Radium–223 Will Change Practice in Metastatic Prostate Cancer
OncologySTAT
Editorial Team. 2011 Oct 14, Interview by L Scott Zoeller
Dr. Parker is consultant in Clinical Oncology at the Royal Marsden Hospital and Honorary Senior Lecturer in Prostate Cancer Translational Research at the Institute of Cancer Research, Sutton, United Kingdom. For more information, view his profile.

OncologySTAT: What is the mechanism of action for radium-223, and how it is administered?

Dr. Parker: The mechanism of action is very simple. Radium, chemically speaking, is just like calcium. They are both in the same group of the periodic table. In the same way that calcium localizes to bone, radium localizes to bone by virtue of its chemical similarity. Radium-223 emits alpha particles. These alpha particles are highly damaging and kill neighboring cells, but they’re extremely short range, a range of less than 100 microns. So, cells at a greater distance than that are spared.

The theory is that radium-223 is injected into the circulation, localizes to bone metastases because it is like calcium, and, then, kills the neighboring cells by virtue of its alpha particle emission. One assumes that it’s effective at killing cancer cells in the bone metastases but that it spares the bone marrow cells, which are just slightly further away. Therefore, you get efficacy against the cancer, but a lack of toxicity to the bone marrow; that’s the theory.

OncologySTAT: Would you talk about the design and results of your recent study evaluating radium-223 in men with symptomatic castration-resistant prostate cancer and bone metastasis?1

Dr. Parker: The trial was called the ALSYMPCA Trial, and it was a phase III randomized trial involving over 900 men. They all had advanced prostate cancer with bone metastases that was progressing after hormone treatment. They were all receiving best standard treatment; that is to say, secondary hormonal treatment, bisphosphonates, if indicated, analgesics, external beam radiotherapy, and whatever else is regarded as best standard treatment.

In addition, they were randomized to receive either radium-223 or placebo. They received six injections once every 4 weeks over a period of 6 months. The main endpoint was overall survival (OS). The key result was that those patients randomized to receive radium-223 had a significant improvement in OS, with a hazard ratio of 0.695, which was highly statistically significant. A key secondary endpoint was time to first skeletal-related event, and that was also significantly improved by radium-223, with a hazard ratio of 0.61. So, these are really substantial benefits in this patient group.

OncologySTAT: What was the toxicity profile of this agent?

Dr. Parker: Radium-223 was remarkably well tolerated. Some patients had mild diarrhea and nausea, but there was no other noticeable acute toxicity. The other thing that was measureable, although not noticeable to patients, was an effect on the bone marrow. Grade III/IV neutropenia was increased from 1% on placebo to 2% on radium-223. Grade III/IV thrombocytopenia was also increased, from 2% on placebo to 4% on radium-223. So, there is a real effect on the bone marrow, although, actually, it’s a very rare effect. Overall, radium-223 prolonged survival and delayed skeletal events, with an extremely favorable toxicity profile.

OncologySTAT: How does this drug fare in terms of symptom control?

Dr. Parker: We didn’t specifically measure symptom control as part of the ALSYMPCA trial. What I can say is that we did measure adverse events and serious adverse events. The ALSYMPCA trial is very unusual in so far as there were fewer adverse events and fewer serious adverse events in patients on radium-223 than there were in patients on placebo. Presumably, this means that there were fewer disease-related adverse events. In other words, there was better symptom control, as well as very few treatment-related adverse events.

There was a previous phase II trial called the BC103 trial,2 which involved about 100 men who were randomized to different doses of radiium-223. The main endpoint of that trial was pain control, which demonstrated that radium-223 is an effective method of pain control in men with bone pain from prostate cancer metastases; however, pain control was not an endpoint of the ALSYMPCA trial.

OncologySTAT: When do you think radium-223 will become available, and how might the results of the ASYMPCA trial impact clinical practice?

Dr. Parker: I do believe that, subject to regulatory approval, ALSYMPCA will change clinical practice. I believe that radium-223 will be approved and will become a standard treatment for men with bone metastases from prostate cancer in the castration-refractory setting. As to when, I really can’t say. If I had to speculate, most drugs take about a year to go through the regulatory process. It does have fast-track designation for FDA approval.3

OncologySTAT: Where do you feel radium-223 will fit best among the newly available agents for advanced prostate cancer?

Dr. Parker: That’s a really important question, and it remains to be seen. The ALSYMPCA trial was unusual in that it included two different subgroups. So, like many other trials, it included patients who had previously received docetaxel, but it also included a group of patients who were unfit for docetaxel, unlike any other phase III trial in prostate cancer, to my knowledge. I think this latter group is very important because we’re fairly confident that only about half of men with advanced prostate cancer ever receive docetaxel. In those men who are considered unfit for docetaxel, then, I think radium-223 will be used relatively early when they progress after their hormone therapy. There really aren’t any other good alternatives in that setting.

However, in the post-docetaxel setting, the arena is somewhat more crowded, with approval of abiraterone and cabazitaxel within the last year or so. Radium-223 will be used, I think, after cabazitaxel, because we don’t know that it would be safe to give cabazitaxel after radium-223. I think we need to get safety data on that.

I happen to think that it would be ideal if one could use radium-223 in combination with abiraterone. In the ALSYMPCA trial, patients were receiving the best hormone treatment available, in addition to radium-223. Of course, at that time, abiraterone was not available, but, it would seem to me, to be in keeping with the philosophy of the ALSYMPCA trial if we were to use radium-223 in men who are receiving abiraterone at the same time. I don’t think there would be any safety issues. They are both extremely well tolerated, and I think that the combination is likely to be highly effective, given that they work in completely different ways.

OncologySTAT: How about using radium-223 with bone-targeted therapy, such as denosumab?

Dr. Parker: That’s another really important question. In the ALSYMPCA trial, a lot of the patients received bone-targeted therapy with zoledronic acid, which was a stratification variable. Radium-223 improved survival in both the groups—in patients who received zoledronic acid and in patients who did not receive zoledronic acid.

I think that radium-223 stands out in contrast to any other bone targeted therapy because it improves survival. Bisphosphonates and denosumab both delay time to skeletal-related events, but neither of them improves survival. Radium-223 not only delays time to skeletal-related events; it also improves survival.

I almost think that the question should be phrased the other way around— what is the role of denosumab in patients who will be receiving radium-223—rather than, what is the role of radium-223 in patients receiving denosumab.

OncologySTAT: So, do you think this is also going to be effective, then, in patients who have other tumor types with bone metastases?

Dr. Parker: In theory, given the mechanism of action, you would expect radium-223 to be effective in patients who have bone metastases from other primary cancers. There is an ongoing phase II trial for women with bone metastases from advanced breast cancer.

OncologySTAT: What other studies are planned or are underway?

Dr. Parker: There is only one other study that is currently underway, and that is a phase I trial at Memorial Sloan-Kettering under Michael Morris, looking at the combination of docetaxel plus radium-223. I have no doubt that there will be future trials of radium-223, but, to my knowledge, there aren’t any underway at the moment.

References

1. Parker C, Heinrich D, O’Sullivan JM, et al. Overall Survival Benefit of Radium-223 Chloride (Alpharadin™) in the Treatment of Patients with Symptomatic Bone Metastases in Castration-resistant Prostate Cancer (CRPC): a Phase III Randomized Trial (ALSYMPCA). Eur J Cancer. September 2011; 47(suppl2):3.

2. Nilsson S, Strang P, Franzén L, et al. A double-blind, randomised dose-response phase II, multicentre study of radium-223 (Alpharadin®) for the palliation of painful bone metastases in castration-refractory prostate cancer patients. Paper resented at: The 2010 European Society of Medical Oncology; October 8-10, 2010; Milan, Italy. Abstract 887P.

3. FDA Grants Fast Track Designation to Radium-223 Chloride for the Treatment of Castration-Resistant Prostate Cancer Patients with Bone Metastases

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