A study published by The Lancet shows that denosumab can slow the spread of prostate cancer to bones in men at high risk of disease progression. The Article is by Professor Matthew R Smith, Massachusetts General Hospital, Cancer Center, Boston, MA, USA, and colleagues.

Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Nearly all men with fatal prostate cancer develop bone metastases and, for most of these men, bone is the dominant or only site of metastases. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases, possibly via a molecular pathway involving the signalling molecule RANKL. Denosumab is a fully human monoclonal antibody that specifically targets, binds and inactivates RANKL.

In this study, the authors analysed the effects of denosumab on bone-metastasis free survival in men with castration-resistant prostate cancer, who had no evidence of bone metastases at baseline, and a high risk of progression based on standard prostate-specific antigen (PSA) tests.

The study enrolled 1432 patients from 319 centres across 30 countries, with 716 assigned to denosumab and 716 to placebo. Denosumab significantly increased bone-metastasis-free survival by a median of over four months compared with placebo (median 29.5 vs 25.2 months). Denosumab also significantly delayed time to first bone metastasis (33.2 vs 29.5 months).

However overall survival was similar in both groups (denosumab 43.9 months, placebo 44.8 months). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis (weakening and destruction of the jaw bone) and hypocalcaemia (dangerously low levels of calcium). 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo, and hypocalcaemia occurred in 12 (2%) of patients on denosumab and two (<1%) on placebo.

The authors say: "Extensive contemporary preclinical research suggests a vicious cycle of complex bidirectional interactions between prostate cancer cells and the bone microenvironment, and tumour–bone interactions have been advanced as the foremost mechanism for the bone-dominant pattern of metastases in prostate cancer."

They conclude: "Improvement in bone-metastasis-free survival and time to first bone metastasis with denosumab treatment in our study shows that a bone-targeted agent can delay time to bone metastasis in men with prostate cancer. Our findings also provide the first direct clinical evidence for the important role of the bone microenvironment and RANKL signalling in the development of bone metastases in men with prostate cancer."

In a linked Comment, Dr Christopher J Logothetis, University of Texas MD Anderson Cancer Center, Houston, TX, USA, says the study should prompt investigators to increase efforts to understand bone metastases in prostate cancer and lead to novel trial designs that select patients likely to benefit from denosumab and similar drugs.

He says: "When should one consider introducing denosumab to the treatment of prostate cancer? The reported findings support its use as an alternative to zoledronic acid, but do not support its broad use as a preventive agent for bone metastases in prostate cancer...The results of the study should serve as a catalyst to accelerate integration of mechanistic insight into study design, with the goal of selection of patient subsets for greatest therapeutic efficacy."

Source: The Lancet