Denosumab is a human monoclonal antibody against the receptor activator of nuclear factor κ-B ligand (RANKL), which is responsible for osteoclast formation, differentiation, and survival. In the Lancet, researchers present the findings of a RCT of denosumab vs. zoledronic acid to treat bone metastases in men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate.
The study involved 1904 participants randomised to 120mg subcutaneous denosumab plus IV placebo (n=950), or 4mg IV zoledronic acid plus subcutaneous placebo (n=951) every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, PSA concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was also assessed for superiority as a secondary endpoint.
The median duration on study at primary analysis cutoff date was 12.2 months for the denosumab group and 11.2 months for those on zoledronic acid. The following findings were reported:
• Median time to first on-study skeletal-related event was 20.7 months with denosumab vs. 17.1 months with zoledronic acid (hazard ratio 0.82, 95% CI 0.71 to 0.95; p=0.0002 for non-inferiority; p=0.008 for superiority).
• Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid.
• More hypocalcaemic events occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0.0001).
• Osteonecrosis of the jaw occurred in 22 [2%] on denosumab and 12 [1%] on zoledronic acid (p=0.09).
The researchers suggest from these findings that denosumab potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
According to an accompanying Comment article, apart from meeting the primary endpoint, the logistical advantages of the use of denosumab over zoledronic acid are clear, as it is easier to give (subcutaneous), allowing for shorter visit times. Furthermore, denosumab reduces the need for management of acute phase reactions and renal monitoring or dose adjustments, although caution should be exercised with patients who have poor baseline kidney function. The authors note that although the results of this trial herald yet another important milestone in the treatment of men with metastatic castration-resistant prostate cancer, several issues come to mind:
• Cost effectiveness trials between zoledronic acid and denosumab have yet to be done.
• With the emergence of newly approved agents for metastatic prostate cancer, the appropriate sequencing of these agents is now a burgeoning question (such as timing of immunotherapy, institution of cytotoxic chemotherapy, or application of novel hormonal agents).
• Although the adverse event profiles are fairly similar for both agents, one notable side-effect is the development of osteonecrosis of the jaw which occurred in more patients on denosumab (though not statistically significantly difference). The exact mechanism by which osteonecrosis of the jaw develops is not entirely understood even for bisphosphonate use, and much less so with denosumab, therefore close monitoring is warranted.
• Further quality-of-life and pain-response data are needed, especially because the most common side-effects of fatigue, bone pain, and asthenia, among others, were reported almost equally in both groups.
The authors of the Comment conclude that despite their questions about the use of denosumab, it remains a welcome addition to the options available for the treatment of metastatic prostate cancer. They also note that trials assessing its use in the delay of onset of metastasis have been promising and will help further define its role in prostate cancer.