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

Institut Gustave Roussy and University of Paris XI, Villejuif, France.
The Journal of urology (Impact Factor: 4.47). 07/2009; 182(2):509-15; discussion 515-6. DOI: 10.1016/j.juro.2009.04.023
Source: PubMed


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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Available from: Tomas Skacel, Jul 03, 2014
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    • "Both have shown similar promise in clinical trials, however only Denosumab is advanced through Phase III. Administration of Denosumab showed significant efficacy by inhibiting osteolysis in patients with prostate or breast cancer bone metastasis, based on the analysis of urinary Ntelopeptide levels as a marker for bone turnover (Fizazi et al., 2009, 2013). A single dosing system of recombinant OPG (AMGN-0007) in a Phase I trial demonstrated a similar sustained reduction in bone lysis (Body et al., 2003). "
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    ABSTRACT: Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor-stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating bone metastasis.
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    • "Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to Denosumab, was reported in one patient. The authors concluded that 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.[2829] "
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    No preview · Article · Mar 2013
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    • "Journal of Bone Oncology denosumab, resulted in significant reductions in the incidence, progress or complications of bone metastases [21] [22] [23]. Despite these significant developments, complications of bone metastases still occur in up to 50% of patients even whilst receiving antiresorptive therapy [1] [4], indicating that there are still significant unmet needs in the prevention and treatment of metastatic bone disease. "
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