Randomized Phase II Trial Of Denosumab In Patients With Bone Metastases From Prostate Cancer, Or Other Neoplasms After Intravenous Bisphosphonates

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 05 Apr 2009 - 0:00 PDT

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UroToday.com - N-telopeptide (uNTx) levels measured the in serum of cancer patients reflect bone turnover, excessive bone resorption and are predictive of skeletal related events (SREs), cancer progression and death. The standard of care is the use of bisphosphonates to stabilize the bone environment of these patients. uNTx levels above 50nmol/L/mM creatinine while on bisphosphonate therapy occurs in 20% of patients and correlates with progression of bone lesions and death. In the online edition of the Journal of Clinical Oncology, Dr. Karim Fizazi and colleagues tested the monoclonal antibody denosumab in patients with bone metastases from prostate, breast and other cancers who continued to have elevated uNTx levels. Denosumab targets the receptor activator of NF-B ligand (RANKL), which mediates osteoclast function and hence bone destruction.

The study was a randomized, open-label, multicenter international trial of patients with confirmed cancers (excluding lung and multiple myeloma) that had at least one bone lesion despite bisphosphonates therapy for at least eight weeks. uNTx was greater than 50nmol/L/mM creatinine and patients were randomized to either continuation of bisphosphonates or subcutaneous denosumab every 4 or 12 weeks. All patients took supplemental calcium and vitamin D. Denosumab was given on day 1 and every 4 weeks (total of 6 doses) or every 12 weeks (total of 2 doses). The primary endpoint was the proportion of patients with uNTx lower than 50nmol/L/mM creatinine at week 13. Several secondary endpoints regarding kinetics of uNTx response and SREs were also assessed.

A total of 111 patients were enrolled from 2004 to 2007. An uNTx <50nmol/L/mM creatinine was reached in 71% of denosumab patients and 29% of bisphosphonates patients. The median reduction in uNTx at week 13 was 78% and 33% in the denosumab and bisphosphonate arms, respectively. At 25 weeks, 64% of patients treated with denosumab maintained uNTx <50 compared with 37% treated with bisphosphonates. The median time to reduction of uNTx to <50 was 9 days for denosumab compared to 65 days for bisphosphonates. A first on-study SRE during the 25-week treatment period occurred in 8% of denosumab patients compared to 17% of bisphosphonates patients. Adverse events were similar between treatments as were the number of patients who died while on study (32-34%). Denosumab given every 4 or 12 weeks resulted in overall similar response rates.

These data are very encouraging for patients with metastatic cancer such as prostate cancer and hold promise to stabilize the complications of bone metastasis.

Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S
J Clin Oncol. 2009 Feb 23. Epub ahead of print.
doi:10.1200/JCO.2008.19.2146

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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