COMMENTARY

Ra-223: New Arrow in Prostate Cancer Quiver

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

Disclosures

June 10, 2013

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In This Article

Introductions

Howard Scher, MD: Hello. I am Howard Scher, Chief of the Genitourinary Oncology Service at the Sydney Kimmel Center for Urologic and Prostate Cancers at the Memorial Sloan-Kettering Cancer Center in New York. Welcome to this edition of Medscape Oncology Insights. Today we will discuss studies in prostate cancer presented at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®). Joining me today is my colleague Johann de Bono, Professor of Experimental Cancer Medicine at the Institute of Cancer Research and Honorary Consultant in Medical Oncology at the Royal Marsden NHS Foundation Trust in Sutton, United Kingdom. Welcome, Johann.

Johann de Bono, MD: Thank you, Howard.

The Fifth New Agent: Ra-223

Dr. Scher: What do you consider the most significant studies from this meeting?

Dr. de Bono: The data presented on radium-223 dichloride (Ra-223; (Alpharadin®)[1,2,3,4,5] are a significant step forward in treating this disease. These data show an improved overall survival, improved quality of life, and a significant impact on skeletal-related events that will significantly affect how we treat advanced prostate cancer.

It is quite impressive that we have had 5 new treatments that improve overall survival in the space of 3 or 4 years, with this being the fifth agent. This agent is US Food and Drug Administration (FDA) approved as of very recently. This will affect practice both in North America and Europe, and more broadly.

Dr. Scher: Can you tell our audience the difference between an alpha-emitter such as Ra-223 and the more traditional beta-emitters that have been used in this context?

Dr. de Bono: Radium is an alpha-emitter. This agent is taken up into the bone by osteoblasts. Essentially the alpha emission results in heavier particles than the beta-emitter. These particles have a much shorter penetration depth. The larger alpha particles also are likely to be more toxic to the tumor cell, more apt to kill the tumor cell. The short depth of penetration of the alpha particle results in less myelosuppression, which is an important feature of this agent.

Having seen this agent given to a lot of my patients in London at the Royal Marsden, with this trial having been led by Chris Parker from our group,[3] we are impressed by the duration of benefit that patients seem to derive from Ra-223. It is a monthly infusion given for 6 months. Further studies are now required to look at giving it for longer durations.

The challenges with radium are to determine what drugs can be combined with it and how we will image and visualize the benefit from radium. Currently, we give the alpha-emitter on a monthly schedule, but we aren't measuring whether the patient has responded or not. Short penetration depth does mean that myelosuppression is much less of an issue than with strontium. However, combining this drug with docetaxel may not be the wisest thing to do, although a combination with hormonal agents such as enzalutamide or abiraterone makes a lot of sense. I would love to hear your thoughts on that.

Dr. Scher: If you think about how the alpha-emitters work, you attach the alpha-emitter to an antibody and then you use it on a sphere of cells; the penetration is only about 3-4 cell layers. If you do it repeatedly, it's analogous to peeling an onion. Does it surprise you that something that has such a short radius of action would actually prolong survival?

Dr. de Bono: We don't yet know how much of an impact Ra-223 will have. We are pursuing a study that is just starting in which we are biopsying all our patients taking Ra-223 to look at how broad the tumor cell kill is around these osteoblastic islands. It suggests that there must be widespread uptake of radium in these tumors.

One important point that you raised is that this agent is dependent on osteoblast uptake. Our patients have disease outside bone. As it is today, this agent would not have an impact for those patients, although immunoconjugate targeting may be a prostate-specific antigen. If such a thing can be generated through a good linker, it would actually be very useful to have for visceral disease. It surprises me that as patients live longer than ever before, we are seeing a lot more visceral disease. At least half of our patients in the last year of life have liver or lung metastases, which used to be quite uncommon.

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