Munich, Germany (UroToday.com) Radium-223 is an alpha emitter which selectively treats bone metastases with alpha radiation1. In a recent GU ASCO oral presentation, a radium-223 pharmacodynamic study demonstrated that higher gamma emission is found in deep tumor containing regions of bone biopsies, compared with superficial regions, supporting the presumed mechanism of radium-2232.
Radium-223 was approved for the treatment of mCRPC in the United States based on the results from ALSYMPCA, a large phase 3 randomized controlled trial where 921 patients were randomized in a 2:1 ratio to receive either radium-223 or placebo. 57% of patients had previously received docetaxel. This trial demonstrated that radium-223 provided benefit for both times to first symptomatic skeletal event (15.6 months vs 9.8 months, HR 0.66, 95% CI, 0.52–0.83, p<0.001) as well as overall survival (14.9 months vs 11.3 months, HR 0.70, 95% CI 0.58–0.83 P<0.001).
Abiraterone is a second-generation anti-androgen medication which inhibits CYP17A1, preventing the production of androgens in the body. Abiraterone has been shown to be effective for patients pre and post docetaxel3,4. In patients prior to chemotherapy, abiraterone significantly improved overall survival compared with placebo (34.7 months, (95% CI 32.7–36.8) vs 30.3 months (28.7–33.3); HR 0.81 (95% CI 0·70–0·93); p=0·0033)4. For patients who have progressed after chemotherapy, overall survival for patients treated with abiraterone was 14.8 months, compared with 10.9 months with placebo (HR 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001)3.
ERA 223 seeks to combine these two widely used therapies, hoping for improved clinical outcomes without adding toxicity, given that the two modes of action and safety profiles are unique. Data from an early access program contained 154 patients who had concomitant use of abiraterone and this appeared to improve median overall survival (NA vs 13 months)5. Non-randomized data also suggests that the use of enzalutamide with Radium-223 is also safe6. This study formally evaluates this combination by randomizing patients to abiraterone 1000 mg daily vs placebo in addition to prednisone 5 mg twice daily. 
806 patients were randomly assigned to either abiraterone + ADT + prednisone (AAP) + Radium-223 or AAP + placebo. Baseline characteristics including age, race, Gleason score, and concurrent use of bisphosphonates was balanced. 
In November of 2017, the study was unblinded early because of a signal of more fractures and deaths in the AAP + radium group and the protocol was amended to allow initiation bisphosphonates. In terms of overall survival analysis, there was no significant difference between AAP + radium-223 and placebo + radium (30.7 months vs 33.3 months, HR 1.195 (95%CI 0.95-1.505, P= 0.128). There was no significant difference between the two groups for the prespecified secondary endpoints, which included radiographic progression-free survival, time to cytotoxic chemotherapy, and time to opiate use for cancer-related pain. There was also no difference in two exploratory endpoints, time to PSA progression and time to deterioration of the quality of life, as defined by the HRQoL.
In terms of treatment-emergent adverse events, there was no difference in total events or grade 3-5 events. However, in terms of specific events, there was a greater number of fractures in the AAP + radium group than placebo + AAP group (26% vs 10%). As expected, patients who had been on bisphosphonates had fewer events than those without, and the protective effect of bisphosphonates applied to both the cohort who received radium and the cohort without radium.
In summary, the addition of radium-223 to first-line abiraterone for patients with mCRPC is not recommended based on the results of this study. Of note, both groups had very limited bisphosphonate prescription at baseline, despite having mCRPC with bony involvement, a well-established indication for skeletal protection6. Future studies may want to consider optimizing bone health for all patients prior to starting investigational combination therapy, as the addition of additional therapy may increase the risk of skeletal events as has been seen in this study. At this time, radium-223 certainly still plays a role in mCRPC, but should not be used as first-line therapy in combination with abiraterone.
Presented by: Matthew R. Smith, MD, Ph.D., Director, Genitourinary Malignancies Program, Massachusetts General Hospital. Boston, US
Invited Discussant: Daniel Heinrich, Consultant, Medical Oncologist at Akershus University Hospital Lørenskog, Norway
References:
1. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine 2013;369:213-23.
2. Armstrong AJ, Gupta S, Healy P, et al. Genomic and phenotypic evidence for prostate cancer osteomimicry in circulating tumor cells from men with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223. American Society of Clinical Oncology; 2018.
3. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England journal of medicine 2011;364:1995-2005.
4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. The Lancet Oncology 2015;16:152-60.
5. O’Sullivan J, Gillesen S, Heidenreich A. Effects of concomitant use of abiraterone and/or enzalutamide with radium-223 on safety and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients treated in an international early access program (EAP). Eur Soc Med Oncol; 2015. p. 25-9.
6. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002;94:1458-68.
Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany