title: 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.
abstract: BACKGROUND
  Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223.
  
  
  METHODS
  In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751.
  
  
  RESULTS
  Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups.
  
  
  CONCLUSIONS
  Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use.
  
  
  BACKGROUND
  Algeta ASA and Bayer HealthCare Pharmaceuticals.
authors.affiliation: Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Electronic address: peterhoskin@nhs.net.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoskin
authors.affiliation: Tulane Cancer Center, New Orleans, LA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.affiliation: Ullevål University Hospital, Oslo, Norway.
authors.forename: Dag Clement
authors.initials: DC
authors.lastname: Johannessen
authors.affiliation: Haukeland University Hospital, Bergen, Norway.
authors.forename: Svein I
authors.initials: SI
authors.lastname: Helle
authors.affiliation: Christie Hospital, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Logue
authors.affiliation: St James's University Hospital, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bottomley
authors.affiliation: Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Wahba
authors.affiliation: Algeta ASA (Bayer), Oslo, Norway.
authors.forename: Anne-Kirsti
authors.initials: AK
authors.lastname: Aksnes
authors.affiliation: The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000188:drug therapy / Q000532:radiotherapy* / Q000556:secondary; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004311:Double-Blind Method; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D011868:Radioisotopes / Q000008:administration & dosage / Q000009:adverse effects; D011883:Radium / Q000008:administration & dosage* / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D011868:Radioisotopes; D043823:Taxoids; D000077143:Docetaxel; C581106:radium Ra 223 dichloride; D011883:Radium