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

Abstract

Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to prevent bone metastasis or death from any cause in men with non-metastatic castration-resistant prostate cancer (CRPC). Methods Men with non-metastatic CRPC at high risk for bone metastasis (PSA ≥8.0 ng/mL and/or PSA doubling time ≤10.0 months) were enrolled in 319 centers from 30 countries. Patients were randomised 1:1 in blinded fashion using an interactive voice response system to receive monthly subcutaneous denosumab 120 mg or placebo. 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. Results 1432 patients were randomised, 716 to receive denosumab and 716 to receive placebo. Denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (hazard ratio 0.85 [0.73–0.98]; P=0.028). Denosumab also significantly delayed time to first bone metastasis (hazard ratio 0.84 [0.71–0.98]; P=0.032). Overall survival was similar between groups (hazard ratio 1.01 [0.85–1.20]; P=0.91). Rates of adverse events (AEs) and serious AEs were generally similar between groups, except for osteonecrosis of jaw (ONJ) and hypocalcemia. Yearly cumulative incidence of ONJ for denosumab was: 1%, 3%, 4% in years 1, 2, 3, respectively; overall, less than 5% (n=33). Hypocalcemia occurred in under 2% (n=12) of denosumab and under 1% (n=2) of placebo patients. The blinded treatment phase has been completed. Conclusion In men with CRPC, denosumab significantly prolonged bone metastasis-free survival and delayed time to bone metastasis. This is the first large randomised study to demonstrate that targeting the bone microenvironment prevents bone metastasis in men with prostate cancer.

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

“…Nevertheless, no meaningful clinical extraskeletal effects have been reported after denosumab administration for osteoporosis, and the overall rate of infections, cancer, and patient mortality have been similar with denosumab use compared with placebo at doses used for the treatment of patients with osteoporosis [5,20]. High-dose denosumab therapy, similar to that used in patients with an unresectable giant cell tumor of bone, was recommended for prevention of skeletal-related events in patients with bone metastasis from a solid tumor [21]. In that study, it was difficult to assess long-term side effects related to denosumab therapy as patients had a limited life expectancy owing to the oncologic disease [21].…”

“…High-dose denosumab therapy, similar to that used in patients with an unresectable giant cell tumor of bone, was recommended for prevention of skeletal-related events in patients with bone metastasis from a solid tumor [21]. In that study, it was difficult to assess long-term side effects related to denosumab therapy as patients had a limited life expectancy owing to the oncologic disease [21].…”

Bone remodeling markers and bone metastases: From cancer research to clinical implications

“…Subsequent studies by the same author using independent data sets found similar conclusions. 67 More recently, denosumab was compared with ZA in patients with BM from several types of solid tumors and multiple myeloma; 1,68,69 in these studies, denosumab was more effective delaying time to first and subsequent SRE, which was correlated with a greater control of bone turnover marker levels (NTX-I and BALP). 1,68 Costa et al 12 further studied the role of bone markers in the diagnosis of disease progression.…”

“…2,70 These phase 2 studies were crucial to select the treatment schedule of denosumab in the three pivotal phase 3 trials that led to the approval of this new BTA. 1,68,69 Despite the evidence that BTAs provide a significant clinical benefit for patients with BM, these drugs are also responsible Bone remodeling markers in bone metastatic disease A Ferreira et al for relevant adverse events, such as hypocalcemia or osteonecrosis of the jaw. 71 Moreover, the rate of adverse events associated with BP treatment increases with time, 71 and only limited evidence assessed long-term use of BPs.…”

CUA-CUOG Guidelines for the Management of Castration Resistant Prostate Cancer (CRPC): 2013 Update

“…27,28 In a recent placebo controlled trial, denosumab significantly increased the bone-metastasis-free survival in patients with non-metastatic CRPC by a median of 4.2 months compared with placebo (29.5 vs. 25.2 months; HR, 0.85; 95% CI, 0.73-0.98; p = 0.028). 32 Denosumab is not approved for bone metastases prevention by Health Canada.…”