Targeting bone metastases in prostate cancer: improving clinical outcome

Abstract

Bone metastases develop in most patients with metastatic castration-resistant prostate cancer (mCRPC). They affect the structural integrity of bone, manifesting as pain and skeletal-related events (SREs), and are the primary cause of patient disability, reduced quality of life (QOL) and death. Understanding the pathophysiology of bone metastases resulted in the development of agents that improve clinical outcome, suggesting that managing both the systemic disease and associated bone events is important. Historically, the treatment of CRPC bone metastases with early radiopharmaceuticals and external beam radiation therapy was largely supportive; however, now, zoledronic acid and denosumab are integral to the therapeutic strategy for mCRPC. These agents substantially reduce skeletal morbidity and improve patient QOL. Radium-223 dichloride is the first bone-targeting agent to show improved survival and reduced pain and symptomatic skeletal events in patients with mCRPC without visceral disease. Five other systemic agents are currently approved for use in mCRPC based on their ability to improve survival. These include the cytotoxic drugs docetaxel and cabazitaxel, the hormone-based therapies, abiraterone and enzalutamide, and the immunotherapeutic vaccine sipuleucel-T. Abiraterone and enzalutamide are able to reduce SREs and improve survival in this setting. Novel agents targeting tumour and bone cells are under clinical development.

The Clinical Efficacy of Radium-223 for Bone Metastasis in Patients with Castration-Resistant Prostate Cancer: An Italian Clinical Experience

“…This result was in line with the published data in ALSYMPCA [15] that rather showed a higher risk of mild to moderate side effects associated with radium-223-based treatment. Considering the short period of time of approximately 1 year and the limited number of patients included in the study, our findings, although not mature, appeared to be consistent with the clinical evidence reported in the literature, assuming that radium-223 is an effective, well-tolerated, and safe treatment in patients affected by CRPC with skeletal metastases and confirming that treatment-associated toxicity was acceptable [28,29].…”

Cancer and the metastatic substrate

“…The other option for these patients is chemotherapy which will be applied depending on which cells the treatment is aimed at. These are divided into three categories: 1) epithelial cells, whose treatment is based on the use of cytotoxic agents such as docetaxel and cabazitaxel [75, 76]; 2) stroma cells which include endothelial, osteoblastic, and osteoclastic cells. The cytotoxics used are thalidomide which is an anti-angiogenic [77]; bevacizuman, a monoclonal antibody against VEGF-A [78]; antrasentan, an osteoblast proliferation inhibitor [79]; denosumab, a monoclonal antibody against RANKL; the activating receptor ligand for the nuclear factor ϰB [80]; zoledronic acid, belongs to the group of bisphonates which inhibit the action of the osteoclasts in the prostate carcinoma cells and encourage an increase in bone density [81, 82]; 3) block the androgen receptor activation or AR which is expressed both in the prostate carcinoma cells and the microenvironment cells.…”

Cuprous oxide nanoparticles inhibit prostate cancer by attenuating the stemness of cancer cells via inhibition of the Wnt signaling pathway

“…Even though abiraterone acetate, enzalutamide, Ra-223 dichloride, and chemotherapy can be used for CRPC therapy, drug resistance often manifests in CRPC patients, and the overall survival benefit is limited. [7][8][9][10] Therefore, there is an urgent need to discover new drugs.…”