Zhishen Ye

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

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.

Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time

PURPOSE Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. PATIENTS AND METHODS A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. RESULTS In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. CONCLUSION Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

6 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (DT) ≤ 10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT < 6 months, a cutoff based on a previous report (Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). METHODS 1432 men with non-metastatic CRPC (baseline [median] PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when > 660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT < 6 months. RESULTS Median BMFS in the placebo group of men with PSADT < 6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT < 6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). CONCLUSIONS Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text].

Denosumab in castration-resistant prostate cancer – Authors' reply

www.thelancet.com Vol 379 May 12, 2012 e50 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ because the benefi ts or harms are determined irrespective of treatment duration. By use of this approach, NNT for bone-metastasis-free survival (where the event is bone metastasis or death) was 21·4 (1/[(370 placebo events/1134·2 placebo patient-years)– (335 denosu mab events/1198·2 denosumab patient-years)]) and NNH for osteo necrosis of the jaw was 38·0 (1/[(33/1254·7)– (0/1206·4)]). On the basis of these calculations, the NNH for osteonecrosis of the jaw is almost twice the NNT for bone-metastasisfree survival, consistent with a favourable benefi t:risk profi le. Additionally, NNT/NNH methods do not take into account any qualitative diff erences between the benefi t and the harm. Bone metastases are irreversible, life-changing events that are systemic in nature, associated with progressive and signifi cant morbidity, and trigger initiation of systemic antineoplastic treatments such as chemotherapy, immune therapy, or second-line hormonal therapy. Osteonecrosis of the jaw is a localised event, and in our study was generally mild to moderate in severity. In patients who developed osteo necrosis of the jaw, no discernible worsening in patient-reported outcomes, including pain, were noted throughout the development of the event, and, by contrast with the statements made by Kyrgidis and Tzellos, dental interventions to treat osteo necrosis of the jaw did not usually require hospital admission. At the time our trial was started, whether denosumab was associated with osteonecrosis of the jaw was not known. Comprehensive measures to detect and adjudicate osteonecrosis of the jaw were put in place, but with no specifi c requirement for preventive dentistry. In accordance with current guidelines for treatment with antiresorptive therapies, patients should have appropriate preventative dentistry before treatment initiation, and maintain good oral hygiene and Denosumab in castration-resistant prostate cancer