Repeated treatment with radium-223 after a first treatment cycle

Radium-223 or Xofigo was first approved in 2013 as “an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.” That meant (and still means) one course of treatment with six cycles of radium-223. However, …

There have for some considerable time been reasons to believe that it is possible to give more than one course of treatment with radium-223 to men with metastatic, castration-resistant prostate cancer (mCRPC), and a paper just published by Sartor et al. in Annals of Oncology now seems to confirm this belief based on data from a cohort of 44 patients with mCRPC that had metastasized to bone, who had been treated with a single, initial course of six injections of radium-223 with no on-treatment bone progression, but who all had subsequent radiologic or clinical progression.

Sartor et al. carried out an international, prospective, Phase I/II clinical trial that enrolled these 44 patients. The primary endpoint of the trial was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and PSA progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression.

Decisions about the use of concomitant therapeutic agents (e.g., agents to treat breakthrough pain; LHRH agonists; antiandrogens; and others) were allowed at the discretion of the investigators, with the exception of chemotherapy and initiation of new abiraterone or enzalutamide.

Here are the core results of the study:

  • 29/44 patients, (66 percent) received all six re-treatment injections.
  • Median time from the prior completion of the patients’ initial radium-223 treatment was 6 months.
  • 41/44 patients (93 percent) reported one or more treatment-emergent adverse events.
  • There were no Grade 4/5 hematologic treatment-emergent adverse events.
  • 1/44 patients (2 percent) exhibited radiographic bone progression while on treatment.
  • 8/44 patients (18 percent) had radiographic soft tissue tumor progression while on treatment (three lymph node metastases and five visceral metastases).
  • Median times to biochemical progression were
    • 2.2 months based on PSA progression
    • Not reached based on total alkaline phosphatase progression
  • Median radiographic progression-free survival was 9.9 months (with a 12.8-month maximum follow-up).
  • 5/44 patients (11 percent) died.
  • 8/44 patients (18 percent) experienced first SSEs.
  • Median overall survival, time to first SSE, and SSE-free survival were not reached.
  • 5/36 evaluable patients (14 percent) had pain progression (based on a baseline worst pain score ≤ 7).
  • After 2 years of follow-up, 28/44 patients (64 percent) patients died, and the median overall survival was 24.4 months.
Sartor et al. conclude that

Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Obviously, one would prefer to find other forms of treatment for men with mCRPC who had already progressed on radium-223 — forms of treatmen t that could both relieve that bone pain and extend their lives with limited risk for complications and side effects. While we are hunting for such forms of treatment, however, we still need to be able to offer appropriate therapy for men progressing after a first course of treatment on radium-223.

Based on this study, we would hope that Bayer would consider a larger trial of repeated radium-223 treatment among men who had already progressed on a first cycle of radium-223. The goal should be to seek approval of such repeated treatment in order to palliate patients’ bone pain and help to maintain their quality of life.


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