Current perspectives on bone metastases in castrate-resistant prostate cancer

Abstract

Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of ²²³radium dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer.

Keywords: Bone metastases; Castrate-resistant prostate cancer; Radium-223; Tumor microenvironment.

Fig. 1

Matrix metalloproteinases (MMPs), chemokine receptor (CXCR)-4, vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF) target metastatic tumor cells to bone and facilitate their survival within the bone microenvironment. Physical factors within bone, including hypoxia, acidic pH, and extracellular Ca²⁺, and bone-derived growth factors, such as tumor growth factor (TGF)-β and insulin-like growth factors (IGFs), activate tumor expression of osteoblast-stimulatory factors, such as VEGF, platelet-derived growth factor (PDGF), and endothelin-1 (ET-1). Osteoclast-stimulatory factors can also be increased, which in turn release factors that promote tumor growth in bone. Republished with permission of the American Association of Cancer Research, from [10]. Permission conveyed through Copyright Clearance Center, Inc.

Fig. 2

Kaplan–Meier estimates of overall survival (OS) show that treatment with Ra-223 increased the median OS significantly relative to placebo, from 11.3 to 14.9 months (P < .001; hazard ratio, 0.70; 95% confidence interval, 0.58–0.83). Republished with permission of [15]. Permission conveyed through Copyright Clearance Center, Inc.