Basel, Switzerland ( Professor Oliver Sartor from Tulane University discussed the impact and utility of radium-223 at today’s bone and bone metastases session at APCCC 2019. Radium-223 first gained prominence with the reporting of the ALSYMPCA trial in 2013. This phase III trial led to FDA approval of radium-223 in the United States for patients with bone mCRPC without visceral metastases1. Patients were enrolled that had two or more bone metastases detected on skeletal scintigraphy, without visceral metastasis who had previously received docetaxel, were docetaxel ineligible, or declined docetaxel. Patients were required to have symptomatic disease based on the requirement for regular analgesics or prior treatment with external beam radiotherapy for cancer-related bone pain in the preceding 12 weeks. There were 921 patients randomized in a 2:1 fashion to radium-223 once every four weeks plus standard of care versus placebo plus standard of care. At an initial, pre-specified, interim analysis when 314 deaths had occurred, there was a longer median overall survival among patients who received radium-223 (14.0 months) than those receiving placebo (11.2 months) with a resulting 30% decrease in the risk of death (HR 0.70, 95% CI 0.55 to 0.88). Following 528 deaths, median overall survival among patients who received radium-223 was 14.9 months compared to 11.3 months for those receiving placebo. Similarly, the updated analysis confirmed a 30% reduction in the risk of death (HR 0.70, 95% CI 0.58 to 0.83) for patients receiving radium-223. Furthermore, radium-223 delayed time to first symptomatic skeletal event (median 15.6 months versus 9.8 months; HR 0.66, 95% CI 0.52 to 0.83).

Dr. Sartor notes that looking back at this trial’s subgroup analyses, it was interesting that there was no benefit for men with less than 6 metastases (HR 0.95, 95% CI 0.46-1.95), and that pathologic fractures still occurred in 4% of patients receiving radium-223 compared to 5% in the placebo arm. In a pre-specified analysis, Dr. Sartor’s group assessed SSE rate as a function of bisphosphonate use in the ALSYMPCA trial, noting that bisphosphonate use at study entry favored radium-223 versus placebo for time to SSE (HR 0.49, 95% CI 0.33-0.74)2. However, when assessing patients without bisphosphonate use at study entry, there was a statistically insignificant benefit of radium-223 to placebo for time to SSE (HR 0.77, 95% CI 0.58-1.02).

Dr. Sartor highlighted what we did and did not learn from ALSYMPCA:

  • Radium-223 was safe and associated with better survival and symptomatic skeletal event rates
  • Concomitant therapies were fine, including external beam radiation or bisphosphonates, and any “old” hormonal agent can be combined with radium-223
  • However, this was before the era of abiraterone, enzalutamide and when imaging was less advanced
  • So, in his opinion, we still had much more to learn

The next question then was: can radium add value to abiraterone or enzalutamide in bone-mCRPC? Two large, phase 3 trials in chemo-naïve patients assessed this question (i) ERA-223, assessing abiraterone +/- radium-223, and (ii) PEACE III, assessing enzalutamide +/- radium-223. ERA-223 randomized 806 patients with chemotherapy-naïve, mCRPC with bone metastasis to radium-223 or placebo in addition to abiraterone acetate3. Symptomatic skeletal event-free survival was the primary outcome. The trial was unblinded prematurely as more fractures and deaths were identified in the radium-223 arm than among patients receiving placebo. Median skeletal event-free survival was 22.3 months (interquartile range 17.0 to 25.8 months) among patients receiving radium-223 and abiraterone acetate and 26.0 months (interquartile range 21.8 months to 28.3 months) in patients receiving placebo and abiraterone acetate (HR 1.12, 95% CI 0.92-1.37). Fractures were more common among patients receiving radium-223 and abiraterone acetate (29%) than those receiving placebo and abiraterone acetate (11%), and time to first fracture significantly favored the placebo arm:

Kaplan Meier Curve for Overall Survival ITTT Analysis

Unfortunately, patients receiving abiraterone + radium-223 also had worse OS compared to patients receiving placebo (HR 1.347, 95% CI 1.047-1.732). As was first evident in the initial ALSYMPA trial that did not demonstrate an OS benefit for men with less than 6 bone metastases, nearly half of the fractures in ERA 223 were in men with less than 6 bone metastases. Additionally, among 76 patients with one or more independently assessed fractures in the radium-223 group, 60 (79%) occurred at a skeletal site with no bone metastasis.

Dr. Sartor provided the following insights from the ERA-223 negative study:

  • Abiraterone and radium-223, started concomitantly, increases fractures and possibly deaths in men with asymptomatic bone metastatic chemotherapy naïve CRPC
  • Fractures occurred across all subsets, but especially those with low volume metastatic disease – most fractures were not at the site of bone metastasis
  • Bone health agents (zoledronic acid and denosumab) substantially decreased risk of fractures

Interim safety results of PEACE-III were recently presented by Dr. Tombal at ASCO 2019, and highlighted by Dr. Sartor in his talk. The phase III EORTC-1333-GUCG/PEACEIII trial is comparing enzalutamide to a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients. After the abiraterone-radium 223 study was prematurely halted, an urgent safety letter was released by the EORTC-1333-GUCG/PEACEIII trial IMDC mandating bone protecting agents among both arms of the EORTC-1333-GUCG/PEACEIII trial. After the mandate, bone protective agent use increased dramatically from 42.6% to 86.7%. The risk of SSE was essentially abolished by mandatory continuous administration of bone protective agents starting at least 6 weeks before the first injection of radium-223, thus emphasizing the importance of treating mCRPC patients with bone protective agents.

Dr. Sartor concluded his talk today with several important take-home messages:

  • Combinations of radium-223 + abiraterone or enzalutamide, used concomitantly, dramatically increase fracture risk in chemotherapy mCRPC men
  • Most fractures in the ERA-223 study occurred at sites without metastases
  • Bone health agents (zoledronic acid or denosumab) dramatically decrease fracture risk in this at-risk population
  • When using radium-223, consider the use of concomitant bone health agents

Presented by: A. Oliver Sartor, MD, Tulane University, New Orleans, Louisiana

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 – 31, 2019 in Basel, Switzerland

1. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

2. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symtomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: Results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014 Jun;15(7):738-746.

3. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419.