Denosumab Treatment Of Prostate Cancer With Bone Metastases And Increased Urine N-Telopeptide Levels After Therapy With Intravenous Bisphosphonates

Main Category: Prostate / Prostate Cancer
Also Included In: Cancer / Oncology;  Urology / Nephrology
Article Date: 10 Aug 2009 - 2:00 PDT

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UroToday.com - Prostate cancer (CaP) has a predilection to metastasize to bone, resulting in skeletal-related events (SREs). The cancer cells interact with osteoclasts (bone resorption), and osteoblasts (bone formation) to create a vicious cycle of tumor growth and bone destruction.

The receptor activator of NF-kB ligand (RANKL) is secreted by osteoblasts in response to tumor cells and is an essential mediator of osteoclast formation, function and survival. Binding of RANKL to its receptor RANK on osteoclasts promotes increased osteoclast formation and bone resorption. Inhibition of RANKL has been shown as beneficial in animal models of bone metastasis.

In the July issue of the Journal of Urology, Dr. Karim Fizazi and colleagues report results of a Phase II trial using denosumab, a monoclonal antibody against RANKL in patients with bone metastasis. The study was a multicenter, phase II, randomized open label, active controlled study conducted at 26 centers in Europe and North America from 2004 to 2008. It compared 2 different doses of subcutaneous denosumab and IV bisphosphonates. Participants had bone metastasis from CaP, other solid tumors except lung cancer, or multiple myeloma.

Urine N-telopeptide (uNTx), a marker of bone turnover is known to correlate with clinical prognosis and was measured. uNTx >50nM BCE/MM creatinine represents excess bone resorption and is associated with increased risk of SREs, cancer progression and death. Denosumab was delivered as 180mg sc every 4 weeks or every 12 weeks and IV bisphosphonates (BP) given every 4 weeks. The primary endpoint was the proportion of patients with uNTx <50 at week 13.

Of the 111 enrolled patients, 50 (45%) had CaP and 49 of these are the basis of this report. Median patient age was 68 years and baseline extent of bone resorption was greater in more patients randomized to denosumab. All patients had prior treatment with zoledronic acid with a median of 6 months treatment before randomization. Half of patients randomized to denosumab and a quarter of men randomized to bisphosphonates had experienced SREs prior to entering the study.

After 13 weeks, suppression of bone resorption was observed in a greater proportion of patients in the denosumab groups than in the IV BP group as demonstrated by the proportion of men with uNTx levels <50 (22 of 32, 69% vs. 3 of 16, 19%) and the median percentage reduction in uNTx levels from baseline (84% vs. 32%). The denosumab-induced reduction in bone resorption was sustained at week 25, with 22 of 32 (69%) patients in the denosumab groups and 5 of 16 (31%) in the IV BP group continuing to have uNTx <50. Denosumab-induced suppression of bone resorption as early as 2 weeks with a median time to reduction of uNTx <50 at 10 days compared with 88 days in the IV BP group. There was 1 SRE (3%) in the denosumab groups compared with 19% in the IV BP.

Adverse events considered potentially treatment related occurred in 9 of 33 (27%) of patients in the denosumab group and 2 of 16 (12%) receiving IV BP. One patient in the denosumab group had grade 4 asymptomatic, reversible hypophosphatemia, possibly treatment related.

In summary, denosumab normalized uNTx more frequently than ongoing IV BP.

Fizazi K, Bosserman L, Gao G, Skacel T, Markus R
J Urol. 2009 Aug;182(2):509-16.
doi:10.1016/j.juro.2009.04.023

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

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