Evidence Supports Earlier Use of Radium-223, Expert Says

Fred Saad, MD

The approved indication for radium-223 dichloride (Xofigo) is for patients with castration-resistant prostate cancer (CRPC) who are symptomatic, have bone metastases, and do not have known visceral metastatic disease.

However, asymptomatic patients may also benefit from radium-223, says Fred Saad, MD, principal scientist, full professor, Department of Surgery, chair in Prostate Cancer Research, Université de Montréal.

“If we wait to treat a patient until the symptom of significant pain occurs, we don’t get as much of a survival benefit because patients are not able to get all 6 cycles,” says Saad. “It is important to start treatment when patients are still in a state that they are able to take a full 6 cycles.”

This concept was recently evaluated in the international early access program (EAP), which compared radium-223 with placebo in 696 patients with CRPC with symptomatic or asymptomatic bone metastases.

In the study, led by Saad, 21% of patients reported no pain, 52% reported mild-to-moderate pain, and 27% reported severe pain. Eighty-eight percent of patients had an ECOG performance status of 0 to 1. Fifty-eight percent of patients were able to receive all 6 radium-223 injections.

Some of the patients in the study were also treated with concomitant therapy: 22% with abiraterone acetate (Zytiga), 20% with denosumab (Xgeva), 18% with bisphosphonates, and 4% with enzalutamide (Xtandi).

The study found that significantly longer overall survival (OS) was observed in patients who had a good ECOG performance status and no pain. OS also appeared to be better in those treated concomitantly with denosumab or abiraterone and radium-223.

OncLive: What were the biggest findings from the EAP?

In an interview with OncLive, Saad discusses the results of the EAP study and how it will shape future studies examining radium-223.Saad: The international EAP involved countries from around the world using radium-223 in a real-world setting. We had the opportunity to study almost 700 patients who were part of this study. We wanted to examine different parameters in patients who were metastatic and castration-resistant. We allowed patients to start radium-223 even if they didn’t have pain coming into the study.

What we realized by looking at patients with pain, without pain, and with mild-to-moderate pain, was that their survival rates were all different. Patients who came in with less pain had significantly improved survival compared with patients with pain.

This led us to believe that patients who start radium-223 earlier in their disease are able to tolerate more cycles, which leads to better outcomes. Patients who come in with very good performance status live longer than those with less good performance status.

The study also gave us the opportunity to investigate concomitant therapy. Patients who came in with radium-223 and abiraterone acetate concomitantly appeared to live significantly longer than those who received radium-223 alone.

At this point, are there any negative effects associated with administering radium-223 to patients earlier?

We also saw a similar result with denosumab; patients who received concomitant denosumab with radium-223 lived longer versus those who received radium-223 alone. That is very intriguing, and it confirms the importance of the prospective phase III international randomized study that we are doing right now with abiraterone with or without radium-223.We haven’t seen any added negative effects. We were very reassured with the international EAP program; it was a real-world setting, and we saw no additional adverse events with radium-223 compared with nearly every other therapy we have for this disease.

What are the most significant benefits from radium-223?

Age is not a restriction and no other factors were really restrictive to patients receiving the agent. It is very well tolerated, and that has been our personal experience at our center, as well. Patients seem to tolerate radium-223, regardless of where they are in the spectrum. Therefore, the important thing is to make sure we treat them when they have a 6-month window, so that they get the full treatment and benefit.In the phase III study, we saw a 30% reduction in the risk of death. In that setting, the patients who were not able to get the full 6 cycles seemed to have less of a benefit. Since this is a bone-targeted therapy, progression-free survival is not a good reflection of activity.

What is on the horizon for radium-223?

Alkaline phosphatase seems to be a much better marker of where activity is occurring, as well as response. When patients get a decrease in alkaline phosphatase, their survival is significantly better than those few patients who don’t get a reduction in alkaline phosphatase. That is what we recommend regarding follow-up of these patients getting radium-223.We need to confirm the added benefit of combining radium-223 with other therapies, such as abiraterone or enzalutamide. There is also a phase II study looking at the safety of combining it with chemotherapy. That looks very promising for now, although it is still not recommended out of clinical trials. There is no worry about giving this agent post-chemotherapy or vice versa. As of now, these sequences seem very safe, both in our experience and in clinical trials.

Saad F, Carles J, Gillessen S, et al. Radium-223 in an international early access program (EAP): effects of concomitant medication on overall survival in metastatic castration-resistant prostate cancer (mCRCP) patients. J Clin Oncol. 2015;33 (suppl; abstr 5034).