COMMENTARY

Ra-223: New Arrow in Prostate Cancer Quiver

Howard I. Scher, MD; Johann S. de Bono, MD

Disclosures

June 10, 2013

In This Article

The Challenge of Measuring Benefit

Dr. Scher: Returning to the mechanism of the alpha-emitters, if you look at the bone morphology in the area of the tumor, it's not as organized or linear (or what is called the "malar bone") as you see normally. You are probably seeing in some cases that the alpha-emitter is distributing throughout a tumor area, so the site of action is not simply the edge of the bone, as we think of it. It’s probably more widespread. Even so, if you look at the prostate-specific antigen (PSA) levels in patients who are treated with radium, and if you look at their bone scans, you are obviously not going to see soft tissue shrinkage because it only works on the bone. How are we supposed to measure that this is actually benefiting someone?

Dr. de Bono: That is a big challenge. The trial that we are just starting not only biopsies the patients pre- and post-therapy but also uses some sophisticated imaging, including multiparametric MRI and PET imaging with choline, as well as bone scans and circulating tumor cells (CTCs). We need to get more information on how to image the benefit from this agent. Is everybody benefitting? Is it possible that because this is a drug that causes DNA damage, cancers with DNA repair defects (and some of these prostate cancers do have that) will be more likely to benefit? Those are the kinds of questions that we are trying to ask in our trials. At this time, we can safely say that we can recommend this agent to our patients on a monthly schedule. I am most impressed with the minimal toxicity from this agent, with minimal myelosuppression, unlike strontium and the beta-emitting compounds. That is a major positive development for our patients.

Dr. Scher: Choline PET is going to image the tumor directly. Have you seen any effects in your studies to suggest that there is a direct antitumor effect?

Dr. de Bono: The data are not yet available to present, but it is going to be very interesting to see whether PET or MRI will allow us to differentiate who is responding. My personal bias is that the multiparametric MRI will be quite useful for this. We have been studying radium preclinically in the bone models of prostate cancer using intratibial injections of the prostate cancer cell line VCaP in mice. This will be an important area, but at present more work needs to be done to further elucidate the imaging question. Whether CTCs are useful, I don't know yet. We don't have the data.

Dr. Scher: We have both used CTCs quite a bit. How do you see the use of these going forward? How robust do you think the data are now to suggest that CTCs should be used at least as a baseline measurement for patients with prostate cancer?

Dr. de Bono: This is a controversial area, but I am convinced that we should be doing CTCs in advanced prostate cancer patients, at least at baseline. With drugs like Ra-223, there would be value in looking further with at least 1 posttreatment test, maybe at 8 to 12 weeks. From our trial results, the data show that this biomarker reflects benefit -- or lack of benefit -- from treatment.

One thing that will challenge us as we have multiple agents is making sure that our patients don't miss out on getting active drugs, as they stay on drugs that are not benefiting them, because the biomarkers that we use (bone scans, PSA levels) are not good enough to differentiate the benefitting from nonbenefitting patients. It is a very important area, and CTCs have much to contribute.

Dr. Scher: As you and I have both shown independently and together in studies of abiraterone[6] and enzalutamide,[7] both of those drugs showed a significant decline in CTCs in patients in whom they were present. Both of those drugs were shown to have a survival benefit in a postchemotherapy population. This is telling us that we have to look beyond the traditional tumor shrinkage and that other ways will be necessary to assess antitumor effects. If you think about the biologic agents, in many cases the effects of the treatment can be quite delayed. The PSA level may not be the most reliable indicator. We have seen in other disease that if you recruit immune cells to a tumor, the tumor might grow on CT scan before there is a resolution.

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