Methods: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
Results: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
Conclusions: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751).
Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Collaborators: Brown M, Dalley D, Dickie G, Dowling A, Elison B, Francis R, Harrup R, Jackson M, Jones E, Kirkwood I, Lin M, Macfarlane D, Martin J, Marx G, Miller A, Pittman K, Pocock N, Pointon O, Roach P, Rossleigh M, Sidhom M, Swift P, Taubman K, Unger S, Woo H, Billiet I, Deconnick H, Duck L, Dumont P, Arouca P, Cabral W, Horizonte B, Caspani A, Horizonte B, Coelho B, Damiao R, Kasai E, Koff W, Moraes AA, Murad A, Horizonte B, Oliveira F, Oliveria L, Sampaio C, Sapienza M, Serrano S, Vilela J, House L, Klotz L, Kuhl J, Leung E, Patel S, Reid R, Simone D, Vitols-McKay M, Bolcak K, Buncova M, Feltl D, Hora M, Kocak I, Kopacek R, Kraft O, Myslivecek M, Pernicka J, Schraml J, Zachoval R, Monnier A, Pecking A, Priou F, Quetu F, Rudenko B, Toubeau M, Wartski M, Zanetta G, Barsegian V, Brunkhorst T, Haese A, Hampel C, Käshammer S, Keil C, Klutmann S, Kranert T, Kuczyk M, Mommsen C, Pfestroff A, Reske S, Sahlmann CO, Schrader A, Strauss A, Truss MC, von Pokrzywnitzki W, Cheng H, Kwong P, Leung A, Leung S, Liu C, Tang F, Yau T, Yuen K, Agranovich S, Ben-Yosef R, Dror Y, Golan H, Levita M, Mechlis-Frish S, Mermershtain W, Sella A, Aglietta M, Amadori D, Ariano M, Asti M, Carrara F, Messina C, Poli G, Possa M, Rossetti C, Salvo D, de Jong A, Roeleveld T, van Riel M, van Tilburg E, Vergunst H, Verhagen P, Aurebekk Å, Bjering K, Boe K, Fredenfeldt T, Grøvnes T, Kasti U, Klepp DO, Larsen K, Nieder C, Pedersen L, Stokkan M, Tvedt B, Chlosta P, Demkow T, Glowa B, Jarzab B, Jarzemski P, Kasprzak K, Klijer R, Kolodziejczyk A, Landwojtowicz M, Mielczarek R, Ochman P, Poniatowicz-Frasunek E, Sowa A, Staszczak, Szczodry A, Zdrojowy R, Zebrowski J, Goh A, Ng C, Tay M, Arpasova M, Balaz V, Breza J, Cano M, Cuperkova J, Cvik M, Lesko J, Mincik I, Reznak I, Spisiakova D, Aranda E, Arbizu J, Banzo J, Bello P, Carles J, Castell J, Donas G, Estorch M, Fombellida J, Gracia P, Latre J, Llarena R, Lomeña F, López R, Maroto P, Mellado B, Mitjavila M, Reynes G, Ruibal Á, Saenz-Cusí A, Axelsson B, Backlund M, Bergström P, Böling B, Falkmer U, Fransson A, Kindblom J, Lagerlund M, Larsson A, Lindgren U, Matscheko G, Starck SA, Anderson P, Bahl A, Bovill R, Chakraborti P, Cox R, Cripps H, Dixit S, Fletcher C, Foley M, Gannon K, Gibbs S, Gilmore B, Graham J, Heath C, Hooper S, Ibbett D, Jenkins C, Jones I, Lawrence G, Money-Kyrle J, Monk D, Mundy J, Murby B, Pascoe S, Przeslak A, Ramachandra P, Randerson S, Richardson A, Robinson A, Scrase C, Scuffham J, Staffurth J, Stockdale A, Sundar S, Vasanthan S, Waldock P, Walton S, Yarrow S, Arredondo S, Garcia-Ramirez J, Hudes G, Lamey R, Michalski J, Mosley D, Obranovich G, Sanders R, Sandler H, Sanford R, Tomblyn M, Vade Streek P.
Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom Reference: N Engl J Med. 2013 Jul 18;369(3):213-23.
PubMed Abstract PMID: 23863050
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