We determined the testosterone castration level with clinical relevance in patients with prostate cancer on continuous androgen deprivation therapy. Secondary objectives were to analyze the role of associated bicalutamide in breakthrough increases of serum testosterone in these patients and the possible benefit of maximal androgen blockade. Serum testosterone was determined 3 times (in 6 months) in 73 patients with nonmetastatic prostate cancer treated with medical castration, 28 (38.4%) of whom also received bicalutamide (maximal androgen blockade). During a mean followup of 51 months (range 12 to 240) 41 (67.1%) events of androgen independent progression were identified, and correlated with breakthrough testosterone increases of 50 ng/dl (classic level) and 20 ng/dl (surgical castration level). Testosterone was less than 20 ng/dl in all determinations in 32 patients (43.6%). Breakthrough increases between 20 and 50 ng/dl were observed in 23 patients (31.5%), and increases greater than 50 ng/dl were observed in the remaining 18 (24.7%). The lowest testosterone level with a significant impact on survival free of androgen independent progression was 32 ng/dl. Mean survival free of androgen independent progression in patients with breakthrough increases greater than 32 ng/dl was 88 months (95% CI 55-121) while it was 137 months (95% CI 104-170) in those without breakthrough increases (p <0.03). Patients on maximal androgen blockade had an incidence of testosterone increase similar to those receiving monotherapy. However, maximal androgen blockade provided a significantly longer survival free of androgen independent progression in those with breakthrough increases greater than 50 ng/dl. In the current report the lowest testosterone castration level with clinical relevance in medically castrated patients with prostate cancer was 32 ng/dl. Breakthrough increases greater than this threshold predicted a lower survival free of androgen independent progression. Maximal androgen blockade might benefit medically castrated cases of prostate cancer with breakthrough increases of more than 50 ng/dl.

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.