ECTS Abstracts (2015) 1 CABS2.1

Radium-223 and skeletal metastases with emphasis on the osteoblastic stroma

Oyvind Bruland


Oslo, Norway.


Skeletal metastases are present in the vast majority of patients with castrate resistant prostate cancer (CRPC). The pronounced bone-tropism of disseminated tumour cells and the sclerotic phenotype of the metastases provide the basis for therapeutic use of bone-seeking radiopharmaceuticals.1 This lecture aims to discuss the mechanisms of action by which the bone-targeting α-emitter 223Ra prolongs overall survival in patients with skeletal metastases form CRPC.2,3 Radium-223 in a chloride formulation deposits high-LET radiation within targeted sites following i.v. injection.4 In a randomized phase-2 trial, where 4 monthly injections of 223Ra were given after external beam radiotherapy to the dominating painful site, a profound reduction of the alkaline phosphatase (ALP) bone-isoenzyme was observed.5 Also a significant decline in prostate-specific antigen was demonstrated with a survival benefit.5 This paved the way for the pivotal phase 3 ALSYMPCA study2 that included 921 CRPC patients with bone METs (223Ra, n=614; placebo, n=307). Here 223Ra significantly improved overall survival vs placebo (median 14.0 months vs 11.2 months; HR=0.695; P=0.002) and was well tolerated. Radium-223 was in 2013 approved by EMA and FDA as the first-in-class α-emitter with a potent, targeted, anti-tumour effect on bone metastases and a favourable safety profile. In a post-hoc analysis,3 223Ra prolonged time to first symptomatic skeletal event vs placebo (median: 15.6 months vs 9.8 months, respectively; HR=0.66; 95% CI 0.52–0.83; P<0.001), and reduced both the risk of external beam radiation therapy for bone pain (HR=0.67; 95% CI 0.53–0.85) and spinal cord compression (HR=0.52; 95% CI 0.29–0.93). At the outset of the 223Ra-development, the prevailing paradigm was that only the reactive zone surrounding the growing skeletal metastases (interphase between bone and cancer) expressed the osteoblastic stroma. In CRPC, however, there is a mesh of reactive stroma avid for 223Ra entwined between cords of carcinoma cells1 with ALP-expression by the CRPC cells per se; due to osteomimicry and epithelial–mesenchymal transition. This may impact on further clinical development of 223Ra.

References:

1. Sartor O, Hoskin P & Bruland OS. Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev 2012 39 (1) 18–26.

2. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013 369 (3) 213–223.

3. Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014 15 (7) 738–746.

4. Bruland ØS, Nilsson S, Fisher DR & Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the α-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 2006 12 (20) 6250s–6257s.

5. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007 8 (7) 587–594.

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