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

Received 22 December 2008 published online 15 June 2009.

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.

Key Words: denosumab, osteoclasts, prostatic neoplasms, RANK ligand, urinary N-telopeptide of type I collagen, human

Abbreviations and Acronyms: AE, adverse event, BCE, bone collagen equivalents, BP, bisphosphonates, Cr, creatinine, ECOG, Eastern Cooperative Oncology Group, IV, intravenous, Q4W, every 4 weeks, Q12W, every 12 weeks, RANKL, receptor activator of nuclear factor κB ligand, SC, subcutaneous, SRE, skeletal related event, uNTx, urine N-telopeptide

a Institut Gustave Roussy and University of Paris XI, Villejuif, France

b Wilshire Oncology Medical Group, La Verne, California

c Amgen Inc., San Francisco, California

d Amgen Inc., Thousand Oaks, California

e Amgen (Europe) GmbH, Zug, Switzerland

Correspondence: Department of Medicine, Institut Gustave Roussy and University of Paris XI, 39 Rue Camille Desmoulins, 94800 Villejuif, France (telephone: 33 1 42 11 43 17; FAX: 33 1 42 11 52 11)

Clinical Trial Registration NCT00104650 (www.clinicaltrials.gov).

Supported by Amgen Inc.

Study received institutional review board/ethics committee approval.

† Financial interest and/or other relationship with Amgen, Novartis, AstraZeneca, Sanofi-Aventis, Ipsen-Beaufour, Pharmion, Bristol Myers Squibb and Takeda.

‡ Financial interest and/or other relationship with Amgen and Pfizer.

§ Financial interest and/or other relationship with Amgen.

PII: S0022-5347(09)00932-X

doi:10.1016/j.juro.2009.04.023

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