Denosumab Most Effective in High-Risk Prostate Cancer Patients

The anti-RANKL antibody denosumab is more effective for preventing bone metastasis in men with high-risk castration-resistant prostate cancer (CRPC) compared with low-risk disease, according to results published in the Journal of Clinical Oncology.

The bone is one of the major sites of metastasis for men with CRPC, and dissemination to this site leads to significant pain. Furthermore, bone metastasis portends mortality for patients, with median survival of metastatic disease ranging from 1.5 to 2 years. Prevention of bone metastasis is therefore a desirable therapeutic goal.

An important promoter of bone metastasis is RANK ligand, which stimulates bone turnover and may help in the homing of prostate cancer cells to the bone. An antibody against RANK ligand, denosumab, was approved for treating skeletal events due to bone metastasis. This study sought to determine a correlation between high-risk disease and denosumab efficacy by analyzing the data taken from denosumab’s phase III prostate cancer trial.

The study analyzed in this work was a phase III, randomized, placebo-controlled trial involving 1,432 men with nonmetastatic CRPC. Patients were then determined to be high-risk if their prostate-specific antigen (PSA) levels were above 8 ng/mL within 3 months of treatment and/or PSA doubling time (PSADT) ≤ 8 months at baseline. The primary endpoint of this study was bone marrow-free survival (BMFS). Secondary endpoints included time to first bone metastasis and overall survival.

PSADT below 8 months appeared to lead to shorter BMFS. Denosumab increased BMFS by 6 months in men with PSADT ≤ 10 months, compared with increases of 7.2 and 7.5 months for PSADT ≤ 6 and ≤ 4 months, respectively. The time to first metastasis was also significantly impacted in each of these PSADT subsets by denosumab, with delays of 6.4, 4.4, and 7.95 months for the ≤ 10, ≤ 6, and ≤ 4 month PSADT subsets, respectively.

Differential impact was not observed in overall survival. Adverse events were not significantly different between the subset groups. This included the most serious expected outcomes of denosumab treatment, hypocalcemia and osteonecrosis of the jaw.

Overall, the paper provides evidence for improved efficacy of denosumab in preventing bone metastasis in CRPC. “The results of these analyses extend the evidence linking PSA kinetics to clinical outcome in men with nonmetastatic CRPC and confirm that short PSADT is a predictor of risk for bone metastasis,” summarized the authors.