Optimal sequence of bone target drugs in metastatic prostatic cancer

Abstract

Breast, prostate, lung and kidney cancer all manifest with a high predilection for metastasis to bone, which is a prevalent cause of morbidity, increased risk of death and decreased quality of life for patients. The avidity of some cancers to grow in bone is because of the peculiar microenvironment predisposed by bone. In metastatic prostate cancer, many novel therapeutic agents are programmed to contrast the signal pathway, including the androgen receptor, osteoclast and stromal inhibitors. Therapy with new drugs in prostate cancer has been shown to decrease the risk of skeletal-related complications and, therefore, provide an overall survival and quality of life benefit. An improved sequence of administration of these drugs may improve efficacy.

Keywords:

• prostate cancer
• bone metastasis
• bisphosphonates
• RANK-L inhibitor
• Ra 223

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Interaction between metastatic cancer cells and bone microenvironment are crucial in the development of bone metastasis.

• Biopsy evaluation of bone metastases shows the presence, next to the cancer tissue, of mature osteoblasts and mineralized matrix.

• Of patients with progressing prostate cancer, almost 90% will develop osteoblastic metastasis in bone, although an osteolytic component is present.

• Understanding the interplay between prostate tumor cells, bone micro-environment and activation of the immune system will likely lead to the treatment of tumor microenvironment of advanced prostate cancer for the prevention of bone metastasis.

• Three new agents have been approved for treatment of bone metastasis in prostate cancer: zoledronic acid (ZA), denosumab and radium dichloride 223 (Ra-223). The latter has demonstrated also a benefit in overall survival while ZA and denosumab, which monitor the activity of osteolytic bone metastases, showed reduced efficacy in prostate disease with osteoblastic lesions compared to what happens to the lytic lesions in other cancers.

• The Ra-223 targets the tumor microenvironment and delivers a potent dose of radiation at sites of bone-forming activity. The efficacy of Ra-223 is attributed to microenvironment targeting.

• Establishing a rational combination sequence on the basis of the clinical trial results, their mechanism of action and the role of the bone in the disease progression is relevant in the clinical practice.

• The key question is the right place of Ra-223 in the sequence of therapy. The optimal timing of Ra-223 administration is still unclear, but recent evidence suggests that in patients with prevalent bone disease this may be administrated prior to docetaxel therapy.

• The combination of Ra-223 and an antiresorptive agent is intriguing considering that concomitant use of denosumab or ZA does not interfere with the beneficial effects of Ra-223 on survival. It could be also of interest to evaluate the association with docetaxel, abiraterone or enzalutamide.