ArticlesDenosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study
Introduction
In western countries, prostate cancer is the most common non-dermatological malignant disease in men. An estimated 217 730 new cases will have been diagnosed in 2010 in the USA1 and 382 250 cases were diagnosed in 2008 in Europe,2 accounting for 28% and 22% of new non-cutaneous cancer diagnoses, respectively. Bone metastases often develop in patients with advanced prostate cancer; the associated complications present a substantial disease and economic burden.3
Since the late 1990s, the assessment of bone-targeted agents for treatment of bone metastases has been based on the endpoint of skeletal-related events, a composite of local skeletal complications consisting of pathological fracture, spinal cord compression, and radiotherapy or surgery to bone. This composite endpoint was the primary endpoint in a phase 3 study in which intravenous zoledronic acid was better than placebo for prevention of skeletal-related events in patients with bone metastases from castration-resistant prostate cancer.4, 5
Although bone metastases from prostate cancer have a predominantly osteoblastic appearance, histological findings6 and analysis of bone turnover markers7, 8 support the view that excess osteoclastic activity induces bone destruction in these metastases.9 RANKL is the main driver of osteoclast formation, function, and survival.10 In-vitro co-culture of prostate cancer cells with osteoblasts produced upregulation of RANKL and downregulation of the endogenous RANKL inhibitor OPG.11 In-vivo inhibition of RANKL in an osteoblastic prostate cancer model also decreased sclerotic changes in the bone.12 Denosumab is a human monoclonal antibody against RANKL; it inhibits osteoclast-mediated bone destruction and is being investigated in clinical studies in men with advanced prostate cancer,13 including for prevention of bone metastases. We undertook a phase 3 study to compare the efficacy and safety of denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer.
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Patients
In this phase 3 study undertaken between May, 2006, and October, 2009, men aged 18 years or older were enrolled from 342 centres in 39 countries worldwide. Eligible patients had histologically confirmed prostate cancer, existing or previous radiographic evidence of at least one bone metastasis, and documented failure of at least one hormonal therapy, indicated by a rising prostate-specific antigen concentration, with a final concentration of 0·4 μg/L or higher within 8 weeks of randomisation in
Results
1904 patients were randomly assigned to treatment between May 12, 2006 and Dec 18, 2008, of whom 951 assigned to receive zoledronic acid and 950 assigned to receive denosumab were eligible for efficacy analyses (figure 1). A protocol amendment on May 5, 2008, increased the sample size by 10% from 1700 to 1870 patients to account for slower than projected enrolment. By the primary analysis cutoff on Oct 30, 2009, about 41 months from the start of enrolment, we expected that about 745 first
Discussion
We have shown that denosumab is better than the established therapy, zoledronic acid, for the delay or prevention of skeletal-related events in patients with advanced prostate cancer (panel). Zoledronic acid is the standard of care, and is better than placebo,5, 18 for prevention of skeletal-related events in men with castration-resistant prostate cancer.5, 18 However, skeletal-related events continue to occur despite treatment with zoledronic acid, albeit at a reduced rate. Zoledronic acid use
References (33)
- et al.
Estimates of cancer incidence and mortality in Europe in 2008
Eur J Cancer
(2010) - et al.
Histopathological assessment of prostate cancer bone osteoblastic metastases
J Urol
(2008) - et al.
Treatment and prevention of bone complications from prostate cancer
Bone
(2011) - et al.
Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate
Eur Urol
(2008) - et al.
Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials
Lancet Oncol
(2009) New research findings on zoledronic acid: survival, pain, and anti-tumour effects
Cancer Treat Rev
(2008)- et al.
Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial
Eur Urol
(2009) - et al.
Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study
Lancet Oncol
(2007) - et al.
Cancer statistics, 2010
CA Cancer J Clin
(2010) - et al.
Economic burden of metastatic bone disease in the U.S.
Cancer
(2007)