ArticlesDenosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
Introduction
Bone metastases are a major cause of morbidity and mortality in men with prostate cancer.1, 2 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.3, 4, 5 Bone metastases pose a substantial health and economic burden because they are associated with skeletal-related events including pathological fractures, spinal cord compression, pain, and need for radiation therapy or surgery to bone.6, 7, 8 Prevention of bone metastasis is an important unmet medical need.
Reciprocal interactions between tumour cells and bone seem to explain the bone-dominant pattern of metastases in prostate cancer.9, 10, 11 In the bone microenvironment, growth factors secreted by tumour cells induce stromal cells and osteoblasts to express RANKL, an essential mediator of osteoclast formation, function, and survival.12, 13, 14 Activation of osteoclasts by RANKL results in increased bone turnover and release of growth factors from bone matrix that might promote establishment of prostate cancer in the skeleton.15 In preclinical models of prostate cancer, osteoclast inhibition prevents bone metastasis.16, 17 RANK expression on prostate cancer cells might also increase metastatic behaviour of tumour cells, with RANKL serving as a potential homing signal to bone marrow.18
Androgen deprivation therapy (ADT) through bilateral orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) agonists or antagonist is standard first-line therapy for metastatic prostate cancer.19, 20 ADT is also often used to treat men with non-metastatic prostate cancer.21 Although initial ADT is uniformly effective, nearly all men with prostate cancer eventually develop castration-resistant disease.22 In men with progressive non-metastatic castration-resistant prostate cancer, high baseline prostate-specific antigen (PSA) and short PSA doubling time are consistently associated with reduced time to first bone metastasis and death.23, 24
Denosumab is a fully human monoclonal antibody that specifically binds and inactivates RANKL. On the basis of superiority to zoledronic acid in breast and prostate cancer,25, 26 denosumab was approved in the USA for the prevention of skeletal-related events in patients with solid tumours and bone metastases.27 We aimed to evaluate the effects of denosumab on bone-metastasis-free survival in men with castration-resistant prostate cancer, no evidence of bone metastases at baseline, and a high risk of progression based on raised PSA or short PSA doubling time.
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Study design and patients
We undertook a phase 3, double-blind, randomised, placebo-controlled study in patients enrolled at 319 centres in 30 countries. Eligible patients were men aged 18 years or older with histologically confirmed prostate cancer, Eastern Cooperative Oncology Group performance status of 1 or less, and adequate organ function. Patients had to have received a bilateral orchiectomy or continuous ADT with a GnRH agonist or antagonist for at least 6 months when entering the study. Patients had to have a
Results
Between Feb 3, 2006, and July 23, 2008, 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo; figure 1). The event-driven date of the primary analysis cutoff was July 30, 2010. Thus, all enrolled patients had a chance to receive investigational product for at least 24 months. The database was locked on Dec 7, 2010, to allow time for radiological confirmation of newly detected bone-scan lesions up to July, 2010, and for data collection and cleaning. Baseline
Discussion
In this global placebo-controlled randomised trial of men with high-risk castration-resistant prostate cancer, treatment with denosumab was associated with improved bone-metastasis-free survival. Treatment with denosumab was also associated with prolonged time to first bone metastasis and with fewer symptomatic bone metastases than was placebo. Several randomised controlled trials have evaluated the effects of other drugs on development of metastases in men with prostate cancer (panel), but
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