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
ABSTRACT 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.
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.
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.
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.
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ABSTRACT: In prostate cancer metastases to bone, cancer cell-derived cytokines stimulate RANKL expression by cells of the osteoblast lineage, which in turn activates osteoclastic bone resorption. However, it is unclear whether cells of the osteoblast lineage signal back to prostate cancer cells, and if so, whether such direct cross-talk can be targeted therapeutically. Using the human prostate cancer cell line, PC3, we identified two novel signalling pathways acting between cells of the osteoblast lineage and cancer cells. First, exposure to RANKL stimulated the expression and release of IL-6 by PC3 cells in vitro (which is known to promote RANKL expression by osteoblasts). Second, treatment of PC3 cells with IL-6 increased the expression of RANK, the cognate receptor of RANKL, and enhanced the RANKL-induced release of IL-6 by PC3 cells. Third, targeted disruption of IL-6 signaling with tocilizumab, a clinically available antibody against the human IL-6 receptor, inhibited skeletal tumor growth in vivo and reduced serum RANKL levels as well as RANK expression by PC3-derived bone tumors. Similar effects were achieved when RANK expression was knocked down in PC3 cells. In contrast, disruption of IL-6 or RANK/RANKL signalling had no effect on PC3 tumor growth in soft tissues, indicating that these signalling pathways act specifically within the bone microenvironment. In conclusion, prostate cancer cells and cells of the osteoblast lineage communicate via two inter-dependent signaling pathways, which through auto-amplification strongly enhance metastatic prostate cancer growth in bone. Both pathways may be targeted for effective therapeutic intervention.Clinical and Experimental Metastasis 09/2014; 31(8). DOI:10.1007/s10585-014-9680-3 · 3.73 Impact Factor
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ABSTRACT: In a phase 3 trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory endpoint. Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks (Q4W), or intravenous zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. Treatment with denosumab significantly reduced the risk of developing first SSE (HR, 0.78; 95% CI, 0.66-0.93; P=0.005) and first and subsequent SSEs (rate ratio, 0.78; 95% CI, 0.65-0.92; P=0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n=48 and n=45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P<0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the endpoint was defined as SSE or SRE. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.Annals of Oncology 11/2014; 26(2). DOI:10.1093/annonc/mdu519 · 6.58 Impact Factor
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ABSTRACT: Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.International Journal of Endocrinology 01/2015; 2015:838202. DOI:10.1155/2015/838202 · 1.52 Impact Factor