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Genitourinary Cancer Editorial Radium223—Where Does It Fit in the Metastatic Castration-resistant Prostate Cancer Treatment Landscape? Tanya B Dorff, MD Assistant Professor of Clinical Medicine, Department of Genitourinary Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, US Abstract Radium223 is approved for symptomatic castration-resistant prostate cancer patients with osseous involvement. Selecting patients and defining sequence strategies are challenging, with the limited available data, but there is a trend toward greater impact in higher volume disease. Combination and/or consolidation strategies for Radium223 will be of significant interest as data emerge from ongoing trials. Keywords Metastatic castration-resistant prostate cancer (mCRPC), symptomatic skeletal-related events (sSRE) Disclosure: Tanya B Dorff, MD, has participated in promotional speaking for Bayer, Astellas, and Sanofi, and has provided consultancy to Dendreon. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 3, 2015 Published online: November 10, 2015 Citation: Oncology & Hematology Review, 2015;11(2):135–6 Correspondence: Tanya B Dorff, MD, Department of Genitourinary Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, US. E: Tanya.Dorff@med.usc.edu After the Food and Drug Administration (FDA) approved docetaxel for metastatic castration-resistant prostate cancer (mCRPC) in 2004, there were limited advances until 2010, when sipuleucel-T marked the first in a series of FDA approvals. Following the addition of immunotherapy (sipuleucel-T), advanced androgen receptor-targeted agents (abiraterone acetate [AA] plus prednisone in 2011 and enzalutamide in 2012), and a new chemotherapy agent (cabazitaxel in 2011), Radium223 received FDA approval for treatment of mCRPC in 2013. The approval was based on the ALSYMPCA trial, 1 in which men with symptomatic osseous metastases from mCRPC who had already received, or were not candidates for, docetaxel were randomly assigned to Radium223, 50 kBq/kg intravenous (IV) once per month, or placebo for six doses. Unlike prior radiopharmaceuticals samarium and strontium, Radium223 treatment was associated with a survival advantage in addition to its palliative benefit. Classification of prostate cancer is evolving as new therapies are approved. The approval of sipuleucel-T led to a new classification of “asymptomatic or minimally symptomatic,” while registrational trials for abiraterone and enzalutamide divided mCRPC according to docetaxel exposure status. The ALSYMPCA data added visceral metastases as an important qualifier. A rough decision tree is depicted in Figure 1. Faced with multiple options, we must now determine which treatment will best meet the needs of an individual patient at each treatment changing time point. Emerging data sets have answered some questions regarding Tou ch MEd ica l MEdia the positioning of Radium223 in mCRPC treatment paradigms, though knowledge gaps remain, as summarized below. Radium223—Before or After Docetaxel? Radium223 prolonged overall survival in the entire population, both docetaxel-pretreated and docetaxel-naïve patients in ALSYMPCA. However, the secondary endpoint of symptomatic skeletal-related events (sSRE) showed a majority of benefit conferred to the docetaxel-pretreated subgroup. 2 The median time to sSRE was 13.5 months in the Radium223 group compared with 7.8 months for placebo in docetaxel-pretreated patients (p=0.00087), whereas the median time to sSRE was 17 months for Radium223 patients and 19.5 months for placebo in docetaxel-naïve patients (p=0.12). While this is a subgroup analysis, warranting cautious interpretation, it is plausible that docetaxel-pretreated patients with bone pain represent an enriched, more aggressive subgroup in which bone targeting therapy may yield a greater impact. However, docetaxel-pretreated patients also have modestly higher rates of hematologic toxicity according to a subgroup analysis of the ALSYMPCA data set. 2 For instance, grade 3 or 4 neutropenia occurred in 11 of 347 (3 %) docetaxel-pretreated patients compared with 2 of 253 (0.8 %) docetaxel-naïve patients, and grade 3 or 4 thrombocytopenia was seen in 31 of 347 (9 %) docetaxel-pretreated patients compared with 7 of 253 (3 %) docetaxel-naïve patients. There was also a higher rate of packed red blood cell transfusion in docetaxel-pretreated patients, which 135