In a recently reported phase 3 trial of men with nonmetastatic castration-resistant prostate cancer (CRPC) and high risk for disease progression based on baseline prostate-specific antigen (PSA) ≥8 ng/mL and/or PSA doubling time of 10 months or less, denosumab (Xgeva)—an anti-RANK ligand monoclonal antibody—significantly increased bone metastasis–free survival (BMFS) and delayed time to first metastasis, but did not improve overall survival (OS) or progression-free survival compared with placebo. In a new exploratory analysis, researchers evaluated the relationship between PSA doubling time and BMFS, time to first bone metastasis, and OS in recipients of denosumab and placebo (Smith MR, et al. J Clin Oncol. 2013;31:3800-3806).
This randomized, phase 3, double-blind, placebo-controlled study included 1432 men with nonmetastatic CRPC. The patients were randomized in a 1:1 ratio to monthly subcutaneous denosumab 120 mg or to placebo. The time of survival without bone metastasis was analyzed according to PSA doubling times of ≤10 months, ≤6 months, and ≤4 months. At baseline, median PSA was 12.3 ng/mL, PSA doubling time was 5.1 months, and doubling duration time was 47.1 months.
An analysis of the placebo arm demonstrated a shorter BMFS time as PSA doubling time decreased to less than 8 months. Compared with placebo, treatment with denosumab was associated with median BMFS increases of 6 months (28.4 vs 22.6 months, respectively; hazard ratio [HR], 0.84) in patients with a PSA doubling time of ≤10 months, 7.2 months (25.9 vs 18.7 months; HR, 0.77) among patients with a PSA doubling time of ≤6 months, and 7.5 months (25.8 vs 18.3 months; HR, 0.71) in patients with a doubling time of ≤4 months.
The median time to first bone metastasis was significantly reduced with denosumab in patients with a PSA doubling time of ≤6 months (26.5 vs 22.1, respectively; HR, 0.80) and ≤4 months (26.4 vs 18.5 months; HR, 0.71). No difference was found in OS between the 2 treatment arms for the overall study population or for PSA doubling time subsets.
These findings demonstrate that faster PSA doubling time is associated with a shorter BMFS in this patient population. Denosumab significantly increased BMFS time and time to first bone metastasis in the overall study population, and the drug has shown the greatest treatment effects in men who are at high risk for disease progression.
Although the study results show that denosumab improves BMFS in patients with nonmetastatic CRPC at high risk for developing bone metastasis, an accompanying editorial by Garraway suggests that denosumab is not approved by the US Food and Drug Administration for the prevention of bone metastasis, in part because of its effect on patient survival, pain metrics, and other quality-of-life measurements (Garraway IP. J Clin Oncol. 2013;31:3838-3840). It is possible that the development of rational therapeutic combinations to prevent bone metastasis, combined with further molecular and genetic classification of prostate cancer, will provide greater clarity regarding who gets treatment and at what point in disease progression, Garraway suggests.
