San Francisco, CA USA (UroToday.com) In May of 2013, the Food and Drug Administration approved radium 223 dichloride (Xofigo) for up to 6 injections for the treatment of patients with castration-resistant prostate cancer (CRPC); symptomatic bone metastases; and no known visceral metastatic disease. 1 FDA approval came after the phase 3 ALSYMPCA trial demonstrated a 30% reduction in the risk of death with Ra-223, versus placebo.2
At the January 2016 ASCO Genitourinary Cancers Symposium in San Francisco, Oliver Sartor, M.D. Medical Director, Tulane Cancer Center and lead investigator on the ALSYMPCA study, presented data that answered one obvious question about Ra-223: namely, if 6 injections of Ra-223 are effective and safe, would more than 6 be as effective, or more effective, and remain safe?3
The data, representing a first experience from an international, multicenter, prospective study in patients with CRPC and bone metastases (mCRPC), confirmed that Ra-223 re-treatment was well-tolerated , offered continued control of disease progression in bone, and was associated with minimal hematologic toxicity to bone.
A total of 44 patients were administered re-therapy with Ra-223. Of this number, 29 (66%) completed the 6-injection therapy. (In addition to Ra-223, all patients had two or more hormonal regimens; 45% had 1 or more chemotherapy regimen. (32 (73%) had failed novel hormonal agents such as abiraterone and enzalutamide.) Baseline characteristics of the patients were comparable to those enrolled in the ALSYMPCA trial.
No new safety concerns emerged and notably, Dr. Sartor said. In fact, the incidence of treatment-emergent adverse events in re-treated patients was comparable or lower than in the ALSYMPCA trial.
“With any trial there are limitations that we have to live with”, Dr. Sartor said in comments to UroToday. “And as we go forward, there’s the question of what have we learned since the phase 3 [ALSYMPCA] study, and what we did not learn in phase III. One of the things we didn’t learn from the phase III study was if there’s a limitation to 6 doses only. Then the question is logically, what happens if you give more?”
Another concern from the ALSYMPCA trial, Dr. Sartor added, was that monitoring was sub-optimal. “One of the other questions is with radium when you give people bone scans and CT scans. What really occurs [with radium] during the administration and after?”
This new trial addressed both issues, he said, and at the ASCO GU meeting, Dr. Sartor presented the first safety and efficacy findings of Ra-223 re-therapy from an international prospective trial in mCRPC.3
“The idea was to simply give radium in a repeat manner up to 6 doses to people who would qualify. The inclusion criteria were very important”, he said. Patients had to have experienced no progression after the next [second] 6 cycles of Ra-223.
Eligible patients had CRPC, two or more metastases to the bone, had completed the 6 initial injections of Ra-223 without experiencing any disease progression in bone and [then] progressed after the initial therapy. Hematologic parameters were to adequate to ensure safety as patients were re-administered the Ra-223
Then patients could go on again. A total of 12 cycles were given to the majority of patients.
Of 44 patients who received Ra-223 for 12 cycles, 29 (66%) completed the therapy. “12 cycles were given to the majority of patients. This had not been done before, Dr. Sartor said. The fact that the majority of patients completed two cycles of Ra-223 reassured the investigators that there we no significant safety signals.
“It was quite nice as regards to safety”, Dr. Sartor said-- a couple of patients with some low platelets, but nothing significant.
“The progression in bone was less than anticipated. And when progression did occur, it was almost all in the soft tissue—not unexpected in a bone-targeted agent.
So, the safety signal was good, and the lack of bone progression was interesting.”
Only had one patient had bone progression. “Of the progressions that occurred, he said, everything was soft tissue – except for the one patient. So, out of 44 patients, to only have one patient [with bone progression] was remarkable and different from what the investigators had expected. “Typically both bone and soft tissue progress”, Dr. Sartor said. “We might have expected half of the patients to progress, or at least, perhaps 30%--to progress. And we had 1 out of 44—closer to 2.5%.”
A larger prospective trial of 12 doses of Ra-223 is accruing patients now.
Ra-223 is “a provocative agent” Dr. Sartor mused, and today it exists in a landscape that includes agents such as abiraterone and enzalutamide. (Ra-223 was studied before the approval of these agents.) “There is now a bit of catch-up to try to understand the implications of working with an agent in the context of an abi and enza-rich environment” he added. Questions of sequencing and combinations arise. Still, with Ra-223, no safety signals have emerged; the median time to serum alkaline phosphatase (ALP) progression was not reached.
1. Xofigo (radium Ra-223 dichloride). Package insert. Available at:
http://hcp.xofigo-us.com/index.php?ecid=xofigo:ps:de:psl:psl:42142:1026
Accessed January 9. 2016.
2. Hoskin P, Sartor O, O’Sullivan JM, et al Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15:1397-1406. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25439694
3. Sartor AO, Heinrich D, Mariados N, et al. Radium-223 (Ra-223) re-treatment (Re-tx): First experience from international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC).
2016 Genitourinary Cancers Symposium. Abstract 197.
*Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles.
Written by: Barbara Jones