Denosumab Treatment of Prostate Cancer With Bone Metastases and Increased Urine N-Telopeptide Levels After Therapy With Intravenous Bisphosphonates: Results of a Randomized Phase II Trial

Purpose: Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. Materials and Methods: Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. Results: Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. Conclusions: In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates.