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 - Abstract

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.

Findings: 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).

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

Funding: Algeta and Bayer HealthCare Pharmaceuticals.

Click HERE to listen to A. Oliver Sartor, MD discuss the results of this trial.

Written by:
Sartor O,1 Coleman R,2 Nilsson S,3 Heinrich D,4 Helle SI,5 O'Sullivan JM,6 Fosså SD,7 Chodacki A,8 Wiechno P,9 Logue J,10 Widmark A,11 Johannessen DC,12 Hoskin P,13 James ND,14 Solberg A,15 Syndikus I,16 Vogelzang NJ,17 O'Bryan-Tear CG,18 Shan M,19 Bruland OS,20 Parker C,21   Are you the author?
1Tulane Cancer Center, New Orleans, LA, USA. Electronic address: .
2Weston Park Hospital, Sheffield Cancer Research Centre, Sheffield, UK.
3Karolinska University Hospital, Radiumhemmet, Stockholm, Sweden.
4Akershus University Hospital, Department of Oncology, Lørenskog, Norway.
5Haukeland University Hospital, Bergen, Norway.
6Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
7Oslo University Hospital, Radiumhospital, Oslo, Norway.
8Hospital Chomutov, Nuclear Medicine Department, Chomutov, Czech Republic.
9Centrum Onkologii-Instytut im Marii Skodowskiej-Curie, Warsaw, Poland.
10Christie Hospital, Manchester, UK.
11Umeå University, Department of Radiation Sciences, Oncology, Sweden.
12Ullevål University Hospital, Oslo, Norway.
13Mount Vernon Hospital Cancer Centre, Northwood, Middlesex, UK.
14Cancer Research Unit, University of Warwick, Coventry, UK; University Hospital, Birmingham NHS Trust, Birmingham, UK.
15St Olavs Hospital, Trondheim, Norway.
16Clatterbridge Cancer Centre, Clatterbridge Health Park, Bebington, Wirral, UK.
17Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
18Algeta ASA, Kjelsaas, Oslo, Norway.
19Bayer Healthcare, Whippany, NJ, USA.
20Norwegian Radium Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway.
21The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK.

Reference: Lancet Oncol. 2014 Jun;15(7):738-46.
doi: 10.1016/S1470-2045(14)70183-4.

PubMed Abstract
PMID: 24836273