Elsevier

The Lancet

Volume 379, Issue 9810, 7–13 January 2012, Pages 39-46
The Lancet

Articles
Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(11)61226-9Get rights and content

Summary

Background

Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer.

Methods

In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091.

Findings

1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.

Interpretation

This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.

Funding

Amgen Inc.

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.

Section snippets

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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