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

We aimed to investigate the safety and efficacy of dutasteride, a 5α-reductase inhibitor, on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance. In our 3 year, randomised, double-blind, placebo-controlled study, undertaken at 65 academic medical centres or outpatient clinics in North America, we enrolled men aged 48–82 years who had low-volume, Gleason score 5–6 prostate cancer and had chosen to be followed up with active surveillance. We randomly allocated participants in a one-to-one ratio, stratified by site and in block sizes of four, to receive once-daily dutasteride 0·5 mg or matching placebo. Participants were followed up for 3 years, with 12-core prostate biopsy samples obtained after 18 months and 3 years. The primary endpoint was time to prostate cancer progression, defined as the number of days between the start of study treatment and the earlier of either pathological progression (in patients with ≥1 biopsy assessment after baseline) or therapeutic progression (start of medical therapy). This trial is registered with ClinicalTrials.gov, number NCT00363311. Between Aug 10, 2006, and March 26, 2007, we randomly allocated 302 participants, of whom 289 (96%) had at least one biopsy procedure after baseline and were included in the primary analysis. By 3 years, 54 (38%) of 144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer progression (pathological or therapeutic; hazard ratio 0·62, 95% CI 0·43–0·89; p=0·009). Incidence of adverse events was much the same between treatment groups. 35 (24%) men in the dutasteride group and 23 (15%) controls had sexual adverse events or breast enlargement or tenderness. Eight (5%) men in the dutasteride group and seven (5%) controls had cardiovascular adverse events, but there were no prostate cancer-related deaths or instances of metastatic disease. Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer. GlaxoSmithKline.

Men receiving androgen-deprivation therapy for nonmetastatic prostate cancer are at high risk for bone loss and fractures. This placebo-controlled study investigated the effects of denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in such men. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. This study investigated the effects of denosumab on bone mineral density and fractures in men receiving androgen-deprivation therapy for prostate cancer. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. Prostate cancer is the most common newly diagnosed cancer in men worldwide. 1 In the United States, prostate cancer accounts for approximately 25% of all new cancer diagnoses and 10% of all deaths from cancer. 2 Androgen-deprivation therapy, through bilateral orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) agonists, is the standard first-line therapy for metastatic prostate cancer. 3 , 4 GnRH agonists are also frequently used to treat men with nonmetastatic prostate cancer. 5 Androgen-deprivation therapy improves disease-free and overall survival in various clinical settings, such as when used as adjuvant treatment in men with locally advanced prostate cancer who are undergoing radiation therapy 6 , . . .

Purpose Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients’ pain, analgesic use, and pain interference with daily functioning. Methods Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials ( N  = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. Results The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. Conclusions SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning.

Purpose This analysis evaluated patient-reported outcomes and analgesic use in patients with bone metastases from solid tumours across three comparative studies of denosumab and zoledronic acid. Methods Pooled data were analysed from three identically designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic acid 4 mg monthly in patients with bone metastases from breast cancer ( n  = 2,046), castration-resistant prostate cancer ( n  = 1,901) or other solid tumours ( n  = 1,597). Pain severity, pain interference, health-related quality of life and analgesic use were quantified. Results At baseline, approximately half of patients had no/mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/2,578] zoledronic acid). Denosumab delayed onset of moderate/severe pain by 1.8 months (median, 6.5 vs 4.7 months; hazard ratio, 0.83; 95 % CI, 0.76–0.92; p  < 0.001; 17 % risk reduction) and clinically meaningful increases in overall pain interference by 2.6 months (median, 10.3 vs 7.7 months; hazard ratio, 0.83; 95 % CI, 0.75–0.92; p  < 0.001; 17 % risk reduction) compared with zoledronic acid. Strong opioid use and worsening of health-related quality of life were less common with denosumab. Conclusions Across three large studies of patients with advanced solid tumours and bone metastases, denosumab prevented progression of pain severity and pain interference more effectively than zoledronic acid.

Background: Denosumab, a fully human monoclonal antibody against RANK ligand, increased bone mineral density (BMD) and reduced fracture risk vs placebo in a phase 3 trial in men with prostate cancer on androgen deprivation therapy (ADT). The present analysis of this study evaluated BMD changes after 36 months in responder subgroups and in individual patients for three key skeletal sites (lumbar spine (LS), femoral neck (FN) and total hip (TH)) and the distal radius. Methods: Men with nonmetastatic prostate cancer receiving ADT were treated with subcutaneous denosumab 60 mg ( n =734) or placebo ( n =734) every 6 months for up to 36 months in a phase 3, randomized, double-blind study. Patients were instructed to take supplemental calcium and vitamin D. For this BMD responder analysis, the primary outcome measure was the percentage change in BMD from baseline to month 36 at the LS, FN and TH as measured by dual-energy X-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a substudy of 309 patients. Results: At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78 vs 17%; FN, 48 vs 13%; TH, 48 vs 6%; distal 1/3 radius, 40 vs 7% ( P <0.0001 for all)). BMD loss at the LS, FN and TH occurred in 1% of denosumab-treated patients vs 42% of placebo patients, and BMD gain at all three sites occurred in 69% of denosumab patients vs 8% of placebo patients. Lower baseline BMD was associated with higher-magnitude BMD responses to denosumab at the LS, FN and TH. Conclusions: In men with prostate cancer receiving ADT, significantly higher BMD response rates were observed with denosumab vs placebo. Patients with lower baseline T-scores benefited the most from denosumab treatment.