Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program.

Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking.

This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline.

Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease.

Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies.

The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.

BMC cancer. 2019 Jan 07*** epublish ***

Axel Heidenreich, Silke Gillessen, Daniel Heinrich, Daniel Keizman, Joe M O'Sullivan, Joan Carles, Manfred Wirth, Kurt Miller, John Reeves, Monica Seger, Sten Nilsson, Fred Saad

Department of Urology, University Hospital Cologne, Cologne, Germany. ., Division of Cancer Sciences, University of Manchester and the Christie, Manchester, UK., Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center, Kfar-Saba, Israel., Department of Clinical Oncology, The Centre for Cancer Research and Cell Biology, Queen's University Belfast and the Northern Ireland Cancer Centre, Belfast, Northern Ireland, UK., Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Department of Urology, University Hospital Carl-Gustav Carus, Dresden, Germany., Department of Urology, Charité University Medicine Berlin, Berlin, Germany., Pharmaceutical Division of Bayer, Whippany, NJ, USA., Department of Oncology, Karolinska University Hospital, Stockholm, Sweden., Department of Urology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.

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