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20-11-2011 | Prostate cancer | Article

Denosumab slows rate of bone metastasis in prostate cancer


Free abstract

MedWire News: Treatment with denosumab is associated with prolonged bone metastasis-free survival times in men with high-risk, castration-resistant prostate cancer, show study data published in The Lancet.

"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," explain Matthew Smith (Massachusetts General Hospital Cancer Center, Boston, USA) and colleagues.

Preclinical studies suggest that osteoclast inhibition might prevent bone metastases, possibly via a molecular pathway involving the signaling molecule receptor activator of nuclear factor kappa-B ligand (RANKL), they add.

In the present study, Smith and team assessed whether denosumab - a fully human anti-RANKL monoclonal antibody that specifically binds and inactivates RANKL - prevents bone metastasis or death in non-metastatic, castration-resistant prostate cancer patients in an international phase III, double-blind, placebo-controlled trial.

A total of 1432 men were randomly assigned to receive treatment with subcutaneous denosumab 120 mg (n=716) or subcutaneous placebo (n=716) every 4 weeks. All of the men were at high risk for bone metastasis based on a prostate-specific antigen (PSA) level of at least 8.0 µg/L, PSA doubling time of 10 months or less, or both.

The researchers report that biochemical markers of bone turnover decreased significantly with denosumab treatment compared with placebo.

In addition, denosumab significantly increased bone metastasis-free survival (time to first occurrence of bone metastasis or death from any cause) by a median of 4.2 months compared with placebo. Patients in the denosumab group experienced bone metastasis free-survival for 29.5 months compared with 25.2 months in the placebo group.

Patients in the denosumab group also had an increased time to first bone metastasis compared with those in the placebo group, at a median of 33.2 versus 29.5 months, and a 33% lower risk for symptoms when metastasis did occur.

However, overall survival did not differ between groups, at a median of 43.9 months for patients in the denosumab group and 44.8 months in the placebo group.

Rates of adverse events and serious adverse events were similar in both groups, at around 10% and 46% respectively, with the exception of osteonecrosis of the jaw and hypocalcemia, which were both higher in the denosumab group.

Indeed, 33 (5%) patients on denosumab developed osteonecrosis of the jaw compared with none on placebo, while hypocalcemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.

Smith and co-authors say: "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."

They conclude: "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, Christopher Logothetis, from the University of Texas MD Anderson Cancer Center in Houston, 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 writes: "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."

By Laura Dean

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