Abstract 6286: The effects of prednisone, abiraterone acetate and radium-223 dichloride on bone in the intratibial LNCaP prostate cancer model
Authors: Suominen Mari I. , Knuuttila Matias , Sjöholm Birgitta , Alhoniemi Esa , Mumberg Dominik , Halleen Jussi M. , Käkönen Sanna-Maria , Scholz Arne 
Published: September 2020

Abstract
Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces double-stranded DNA breaks in cancer cells, osteoblasts, and osteoclasts. Ra-223 showed survival benefit in patients with bone-metastatic castration-resistant prostate cancer in a pivotal phase 3 trial. Recently, in a phase 3 trial of Ra-223 in combination with abiraterone acetate (AA) and prednisone/prednisolone (P), an increased risk of fractures was observed, which could be largely diminished by concurrent administration of bone resorption-inhibiting bisphosphonates or denosumab.
The aim of this study was to investigate the effects of vehicle, Ra-223, AA, P, AA/P, and Ra-223/AA/P on bone using a mouse model mimicking osteoblastic prostate cancer bone metastases.
Male NOD.scid mice were injected intratibially with LNCaP cells. Following stratification based on serum PSA and total bone volume of the tumor-bearing tibia, mice were treated for 28 days. Serum TRACP 5b and PSA levels were measured at multiple time points. At sacrifice, hind limbs were collected to analyze healthy and tumor-bearing bone structure, quality and formation rate by microCT, 3-point bending assay and dynamic histomorphometry, respectively. Also, Ra-223 incorporation was measured.
Treatment with AA/P reduced Ra-223 incorporation to bone. PSA levels were similarly reduced at sacrifice upon Ra-223, AA, AA/P, and Ra-223/AA/P treatment indicating the absence of triple combination-specific additive anti-tumor effects. Bone resorption marker TRACP 5b levels increased transiently during the first two weeks of Ra-223/AA/P treatment. Neither bone structure or bone biomechanical quality in healthy or tumor-bearing tibia were affected by Ra-223/AA/P. Regarding dynamic bone formation, trabecular mineralizing surface (MS) was reduced in all groups containing Ra-223, while periosteal MS was reduced in all groups receiving P. However, only Ra-223/AA/P reduced both trabecular and periosteal MS. In line with the inhibition of dynamic bone formation, Ra-223/AA/P treatment decreased the number of osteoblasts.
The AA/P treatment-induced reduction of Ra-223 incorporation may mediate the lack of additive anti-tumor effects in the Ra-223/AA/P group. Regarding bone health, Ra-223/AA/P specifically induced a transient increase in bone resorption and inhibited both periosteal and trabecular new bone formation but did not lead to structural or biomechanical bone changes. This preclinical mechanism may nevertheless contribute to the increased fragility observed in the clinics and may explain the beneficial clinical effects of bone resorption-inhibiting bisphosphonates and denosumab. However, several species- and model-related factors may limit the translational relevance of these findings.
Citation Format: Mari I. Suominen, Matias Knuuttila, Birgitta Sjöholm, Esa Alhoniemi, Dominik Mumberg, Jussi M. Halleen, Sanna-Maria Käkönen, Arne Scholz. The effects of prednisone, abiraterone acetate and radium-223 dichloride on bone in the intratibial LNCaP prostate cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6286.