Abstract 688: Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models

Abstract

Abstract Radium-223 dichloride (radium-223) is a targeted alpha therapy that binds to newly formed abnormal bone in bone metastases and induces DNA double-strand breaks (DSBs) in cancer cells, osteoblasts and osteoclasts. Radium-223 is used for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Darolutamide is an androgen receptor inhibitor indicated for patients with metastatic hormone-sensitive prostate cancer or non-metastatic CRPC. We studied the antitumor effects of radium-223 in combination with darolutamide using LNCaP human prostate cancer cells in vitro and an intratibial LNCaP model mimicking prostate cancer metastasized to bone. The in vitro antiproliferative effects of radium-223 and darolutamide were determined using LNCaP cells. Gene set enrichment analysis (GSEA) was conducted on RNA sequencing data from LNCaP cells treated with the synthetic androgen R1881 alone or in combination with darolutamide. LNCaP cells were inoculated into the right tibia of male NOD.scid mice. The mice (n=7-9/group) were randomized based on serum prostate-specific antigen (PSA) and treated with vehicle, radium-223 (330 kBq/kg, Q4Wx2, i.v.), darolutamide (100 mg/kg, BID, p.o.), or with a combination of radium-223 and darolutamide, for 41 days. PSA and the bone turnover markers PINP and CTX-I were measured every second week in serum. Tumor-induced abnormal bone area, bone formation rate and radium-223 uptake in tumor-bearing tibiae were determined by X-ray, histomorphometry and gamma counter, respectively. The combination of radium-223 and darolutamide showed synergistic antiproliferative effects with combination indexes between 0.69-0.75 in vitro. GSEA demonstrated a prominent darolutamide-induced downregulation of DNA damage response (DDR) signaling pathways. In vivo, the combination treatment showed synergistic antitumor efficacy (p=0.04) as demonstrated by lower PSA concentrations when compared with the vehicle, radium-223 or darolutamide monotherapies (p=0.004, p=0.011 and p=0.002, respectively). In the vehicle and combination treatment groups, the mean serum PSA was 541% and 95.9% of the pre-treatment level, respectively. Furthermore, radium-223 alone or in combination with darolutamide inhibited increased bone turnover, tumor-induced abnormal bone growth and trabecular bone formation when compared to vehicle. Concurrent administration of darolutamide did not affect radium-223 uptake in tibiae. Radium-223 in combination with darolutamide exhibited synergistic antitumor efficacy both in vitro and in vivo. The synergistic effects could be due to the radiosensitization of cancer cells by darolutamide-induced downregulation of DDR pathways. Our results suggest that the combination of targeted alpha therapy with an androgen receptor inhibitor is a promising treatment strategy for mCRPC. Citation Format: Christoph A. Schatz, Mari I. Suominen, Andreas Schlicker, Matias Knuuttila, Esa Alhoniemi, Sanna-Maria Käkönen, Bernard Haendler, Urs B. Hagemann, Arne Scholz. Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 688.