Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.
BACKGROUND
Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.


METHODS
In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.


RESULTS
Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).


CONCLUSIONS
Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.


BACKGROUND
Algeta and Bayer HealthCare Pharmaceuticals.
Tulane Cancer Center, New Orleans, LA, USA. Electronic address: osartor@tulane.edu.
Oliver
O
Sartor
Weston Park Hospital, Sheffield Cancer Research Centre, Sheffield, UK.
Robert
R
Coleman
Karolinska University Hospital, Radiumhemmet, Stockholm, Sweden.
Sten
S
Nilsson
Akershus University Hospital, Department of Oncology, Lørenskog, Norway.
Daniel
D
Heinrich
Haukeland University Hospital, Bergen, Norway.
Svein I
SI
Helle
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
Joe M
JM
O'Sullivan
Oslo University Hospital, Radiumhospital, Oslo, Norway.
Sophie D
SD
Fosså
Hospital Chomutov, Nuclear Medicine Department, Chomutov, Czech Republic.
Aleš
A
Chodacki
Centrum Onkologii-Instytut im Marii Skodowskiej-Curie, Warsaw, Poland.
Paweł
P
Wiechno
Christie Hospital, Manchester, UK.
John
J
Logue
Umeå University, Department of Radiation Sciences, Oncology, Sweden.
Anders
A
Widmark
Ullevål University Hospital, Oslo, Norway.
Dag Clement
DC
Johannessen
Mount Vernon Hospital Cancer Centre, Northwood, Middlesex, UK.
Peter
P
Hoskin
Cancer Research Unit, University of Warwick, Coventry, UK; University Hospital, Birmingham NHS Trust, Birmingham, UK.
Nicholas D
ND
James
St Olavs Hospital, Trondheim, Norway.
Arne
A
Solberg
Clatterbridge Cancer Centre, Clatterbridge Health Park, Bebington, Wirral, UK.
Isabel
I
Syndikus
Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
Nicholas J
NJ
Vogelzang
Algeta ASA, Kjelsaas, Oslo, Norway.
C Gillies
CG
O'Bryan-Tear
Bayer Healthcare, Whippany, NJ, USA.
Minghua
M
Shan
Norwegian Radium Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway.
Øyvind S
ØS
Bruland
The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK.
Christopher
C
Parker
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology* / Q000532:radiotherapy; D011883:Radium / Q000627:therapeutic use*
D011883:Radium