Use of Radium-223 Continues to Evolve in mCRPC

Michael Morris, MD

In May 2013, radium-223 dichloride (Xofigo), became the first alpha-emitting radiopharmaceutical approved by the FDA for patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases.

The approval was based on the phase III ALSYMPCA trial, which demonstrated an overall survival (OS) rate of 14 months for patients who received radium-223 compared with 11.2 months in patients who received placebo. The agent also delivered an improvement in the median time to first symptomatic bone metastases event with 13.6 months and 8.4 months to first event with radium-223 versus placebo, respectively.

Since then, the therapy—which selectively targets bone metastases with high-energy, short-range alpha particles—has continued to show positive survival benefit and improved quality of life in men with mCRPC.

Following the ALSYMPCA trial, an international expanded access program (EAP) examined 696 patients with bone mCRPC. Patients were permitted to receive concomitant therapy, with 22% of those receiving concomitant therapy on abiraterone acetate (Zytiga), 20% on denosumab, 18% on bisphosphonates, and 4% on enzalutamide (Xtandi), in addition to radium-223.

At the time of analysis, median OS was 16 months, and medium time to first symptomatic skeletal-related event (SSE) was 18 months. Ad hoc analysis found that OS was statistically significantly longer in patients with concomitant denosumab and concomitant abiraterone.

Based on the results of this trial, combination treatments with radium-223 are now being considered. The phase III ERA 223 study, which is currently recruiting participants, is investigating the use of radium-223 in combination with abiraterone and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone predominant mCRPC.

OncLive: Can you explain the mechanism of action for radiopharmaceuticals like radium-223?

What are the biggest benefits of radium-223?

How has the field of radiopharmaceuticals evolved in recent times?

What is on the horizon for the use of radium-223 and other radiopharmaceuticals?

To better understand the potential of radium-223 and how the agent could be successful and impactful in mCRPC, OncLive spoke with Michael Morris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.Morris: Radiopharmaceuticals deliver targeted radiation therapy to either the tumor itself or compartments that contain the tumor. The whole idea behind a bone-seeking radiopharmaceutical is that it targets the component of the body that contains the primary site of metastatic disease, which, in prostate cancer, is the bone. It delivers radiation therapy to the bone, and since that is where most of the prostate cancer has localized, it is in turn treating most of the metastatic compartment of the disease. It delivers a very specific type of radiation therapy to the bone, which is an alpha-emitting radiation therapy or alpha particle. This has unique characteristics that minimize toxicity while maximizing treatment effect.This drug has been shown to prolong survival and improve quality of life in men with mCRPC. It improves overall survival; therefore, it helps patients live longer. It also delays complications related to bone metastases, known as SSE. These include bone fracture, bone pain, spinal cord compression, and others. Nevertheless, the drug is not only helping patients live longer, but it is helping them live better, as well.Radiopharmaceuticals have been around for a very long time. The biology behind them is really straightforward and relates to the chemistry of bone. The whole idea of replacing some of those components with radioactive components has been around for a while; the difference is that previous bone-seeking radiopharmaceuticals admitted a particle of energy known as a beta particle rather than an alpha particle. Beta particles have deeper tissue penetration, more side effects, and have never been shown definitively to improve survival. Now, we have an alpha particle, which has very shallow tissue penetration, has fewer side effects, and prolongs survival.Combining radium-223 with other types of treatment that directly target the cancer may be the future, whether that is androgen receptor—directed therapy, chemotherapy, or novel therapeutics that are yet to be developed. There is currently a study of radium-223 and abiraterone. There is also a study of radium-223 with chemotherapy that is under discussion that we hope to open shortly. In terms of new therapeutics, radium-223 is a DNA-damaging agent, and there is new data showing that patients that have BRCA2 mutations are very responsive to PARP inhibitors. Therefore, there is an idea to give radium-223 with a PARP inhibitor.

What should an oncologist considering radium-223 for patients with prostate cancer know about the drug?

Work is also still being done on optimizing how to administer radium-223 alone, how frequently patients should receive it, how long, and at what dose. All of those things are still being refined and optimized, and there are various clinical trials looking at those questions. Over the next few years, we should have more information regarding optimization of the drug alone and how to sequence or combine it with other drugs.They should know how to give it and how to interpret its treatment effects. That is tricky for many treatments but, in particular, it is tricky with this drug because you do not necessarily have a good sense of who is responding and who is not responding, because there is no imaging data to follow, that we know of. Oncologists also need to understand which patients should get this drug, which requires coordinating with someone who has experience with either radiation oncology or nuclear medicine.