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Fracture Risk in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Radium-223

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(UroToday.com) Radium 223 (Ra223) is a bone-seeking, alpha-emitting radionuclide that has been shown to improve overall survival and time to skeletal-related events in men with metastatic castrate-resistant prostate cancer (mCRPC)1. In the prospective, phase 3, randomized trial (ERA 223), the combination of Ra 223, abiraterone acetate, and prednisolone was associated with an increased risk of fracture compared with abiraterone acetate, prednisolone, and placebo2

The presented REASURE study is a prospective phase 2 trial that randomized patients between two different dose levels of Ra 223 while incorporating routine imaging with diffusion-weighted whole-body MRI (DW WBMRI) for response assessment. In this study, the authors conducted an exploratory analysis, looking into the fracture rate among patients treated with Ra 223 monotherapy. The REASURE trial is a registered trial (ISRCTN17805587) co-sponsored by The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.

In this study, chemotherapy-naïve patients with bone-only progressive mCRPC disease were randomized to one of two Ra 223 dose-levels; 55 or 88 kBq/Kg, q4 weeks for six cycles. DW WBMRI scans were done at baseline, at cycles 2 and 4, and 1-month post-treatment. Patients were evaluated every four months for one year, with routine imaging performed according to routine clinical practice. All scans were collected and reviewed centrally. The authors specifically examined the time to new fractures from baseline. The time to fracture was analyzed using Kaplan Meier curves, and associations with other variables were assessed using log-rank tests and Cox-Proportional Hazards.

A total of 36 patients were evaluable for this analysis. The median follow-up time was 16.3 months. The baseline patient characteristics are shown in table 1. Only four patients were treated with bone-health agents. Eighteen patients (50%) were previously treated with corticosteroids. Overall, 74 fractures were identified in 20 (56%) patients. Ten patients had symptomatic fractures, 4 had asymptomatic fractures, and six patients had an indeterminate symptomatic status. Most fractures occurred in the axial skeleton and in bones without metastatic deposits (68%), as seen in Table 2.  The Kaplan Meier curve assessing fracture risk is shown in Figure 1. Lastly, the Cox regression analysis of both the univariable and multivariable analyses are shown in Table 3, not showing any significant statistical benefit to the higher Ra223 dose in reducing fracture risk. Only prior corticosteroid use was associated with an increased fracture risk on multivariable analysis.

Table 1 – Baseline patient characteristics:

ESMO2020_Adham_Hija_Ra223_1.png

Table 2 – Fracture location and distribution:

ESMO2020_Adham_Hija_Ra223_2.png

Figure 1 – Kaplan Meier curve of fracture risk:

ESMO2020_Adham_Hija_Ra223_3.png

Table 3 – Univariable and multivariable analyses assessing the risk of fracture:

ESMO2020_Adham_Hija_Ra223_4.png

In conclusion, fractures are commonly seen on MRI during and after Ra 223 treatment. At least 50% of fractures were shown to be symptomatic. According to the authors, the current findings underscore the importance of utilizing bone-protecting agents for the prevention of fragility fractures in men with mCRPC treated with Ra 223.

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(3): 213-23.
2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology 2019; 20(3): 408-19.

Presented by: Adham Hijab, The Royal Marsden NHS Foundation Trust, London, United Kingdom

Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept – 21 Sept 2020 

Related Content: 
Decreased Fracture Rate When Adding Bone Protecting Agents to Radium-223: PEACE III – Bertrand Tombal
ASCO 2019: Decreased Fracture Rate by Mandating Bone-protecting Agents in the EORTC 1333/PEACE III Trial
APCCC 2019: Radium-223 and Bone Health Agents: Lessons Learned
A Renewed Analysis of ERA 223 – Fred Saad

 

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