Radium-223 Combinations on Horizon in mCRPC

Oliver Sartor, MD

Now that extensive data are available on radium-223 dichloride (Xofigo) and its associated survival and quality-of-life benefits in patients with metastatic castration-resistant prostate cancer (mCRPC), it is time to explore the agent’s potential in combination with other therapies, explains Oliver Sartor, MD.

The radiopharmaceutical’s FDA approval in May 2013 was based on findings from the phase III ALSYMPCA trial.¹ In the study, radium-223 demonstrated a median overall survival (OS) of 14.9 months compared with 11.3 months with placebo for patients with bone-metastatic CRPC (HR, 0.70; P <.001). Additionally, radium-223 was associated with a significant delay in both the median time to first symptomatic skeletal-related events and the time to an increase in the PSA level.

However, other ongoing studies are seeking more possibilities with the agent, such as a phase III trial randomizing patients with bone predominant mCRPC to either radium-223 alone or radium-223 with abiraterone acetate (Zytiga) and prednisone.²

A second ongoing study³ is investigating the efficacy and safety of radium-223 in combination with abiraterone or enzalutamide (Xtandi) in patients with mCRPC. The phase IIa randomized study is evaluating bone-scan response in patients following treatment, as well as radiological progression-free survival, OS, and skeletal events.

OncLive: What is the current mindset with radium-223?

What were some things we did and did not learn from the ALSYMPCA trial?

In an interview with OncLive, Sartor, medical director of Tulane Cancer Center, discusses the combination regimens being explored with radium-223, its unique mechanism of action, and the associated risks and benefits.Sartor: There are insights we have gained since the phase III ALSYMPCA trial. There are a lot of lessons we did learn in the trial, but there is also an understanding of what we did not learn. We are extending the data up through the contemporary setting in 2016.We learned that radium-223 is able to prolong survival, it is able to decrease symptomatic skeletal events, and that it is safe.

However, we did not learn anything about abiraterone or enzalutamide combinations with radium-223, or even denosumab combinations with radium-223.

What are going to be the next steps?

Now, I have begun to present some data that would indicate that utilization with denosumab is safe and may be effective. There is also a little bit of interesting data on abiraterone combined with radium-223. We are just extending beyond the original phase III data and having provocative data on these provocative points.We need to do formal clinical trials to be able to assess things such as abiraterone with or without radium-223, and enzalutamide with or without radium-223. Also, we need to better understand the timing of radium-223 administration.

What is the optimal use of radium-223?

In our next steps, we need to formalize the treatment plans, begin to offer new combinations, look at retreatment of radium-223, and give it at higher doses. There are many places we can go with treatment of prostate cancer.We need to use it when patients are able to receive 5 or 6 doses of radium-223. I see too much use of radium-223 where people are only getting 1, 2, or 3 doses. You cannot prolong survival with only a minimum number of doses.

How does the mechanism of action of radium-223 compare with that of other agents in prostate cancer?

If you were going to look at radium-223 in a broad sense, it is a bone-targeted agent. Therefore, you have to remember it is optimal in an osteoblastic bone-targeted disease. You need to be able to give radium-223 along with a concomitant hormone therapy that will be effective. The patients who are going to have some benefit are those with a lot of bone relative to soft tissue, as well as patients who are in their first-, second-, or third-line of therapy. Those are the patients who I am thinking could receive radium-223.It really is a completely unique mechanism of action. It binds to hydroxy-apatite in newly formed bones of osteoblastic lesions. It doesn’t bind to the tumor per se, but it radiates the tumor microenvironment in these osteoblastic areas.

What are the risks reported with radium-223?

What else is on the horizon with this radiopharmaceutical?

I don’t think we fully understand the mechanism of action of radium-223, because it may have an antiangiogenic effect, a proimmune effect, and it might be able to have a microenvironmental effect on the osteoblast that we don’t understand. Nevertheless, we know that it does work. From here, we can kind of go forward.The risks predominantly include a 7% risk of grade 3/4 thrombocytopenia. That doesn’t sound very high, but it can be very significant when it happens in an individual patient. It does not have any high risk of anemia. It does come with a tiny bit of leukopenia, diarrhea, and fatigue—in my experience. Overall, it is a very well-tolerated agent.We need to be able to bring it forward in clinical trials—particularly testing it in combination and exploring it in higher and longer doses. It is also going to migrate over to other diseases, such as osteosarcoma. It will need to be proven, but there are enough anecdotes that, in something like osteosarcoma, radium-223 might show potential as a treatment.

It is an interesting agent, but I think we need to take the alpha particles forward in a targeted fashion, move it away from the bone and closer to the tumor, and use things such as a targeted alpha-emitter. There are some products in development that are quite interesting.

References

1. Parker C, Nilsson S, Heinrich D, et al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer with bone metastases (ALSYMPCA). J Clin Oncol. 2012;30(suppl; abstr LBA4512).
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02043678
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02034552