Prostate cancer agent increases bone metastasis-free survival

San Francisco-PSA kinetics can be used to identify patients with nonmetastatic castration-resistant prostate cancer (CRPC) who are at enhanced risk for bone metastases or death, results of a recent global randomized controlled trial indicate.

In addition, in patients found to have aggressive PSA kinetics, the human monoclonal antibody denosumab (XGEVA) given monthly can delay the development of bone metastases or death, according to results from the exploratory analysis, which was presented at the 2012 Genitourinary Cancers Symposium in San Francisco and published in the Lancet (2012; 379:39-46).

Denosumab significantly increased bone metastasis-free survival in men with CRPC at high risk for bone metastases based on a PSA value ≥8.0 ng/mL and/or a PSA doubling time of 10 months or less in a randomized controlled clinical trial of 1,432 patients with CRPC and no detectable bone metastases at baseline. About half of the subjects in the study met both eligibility criteria.

First author Matthew R. Smith, MD, PhD, and co-authors performed additional analyses of the trial to evaluate the risk of bone metastasis according to PSA doubling time in patients who were randomized to placebo in the trial and the efficacy of denosumab based on PSA doubling time.

Among the 147 placebo recipients in the trial, "There was a steep rise in the incidence of bone metastasis or death with an inflection point starting at about 8 months," said Dr. Smith, professor of medicine at Harvard Medical School and assistant in medicine, hematology/oncology at Massachusetts General Hospital Cancer Center, Boston.

Further analyses were conducted in subsets of patients at particularly high risk based on their PSA doubling times.

Decreases in risk of bone metastases, death

In the subset of patients with a PSA doubling time of 10 months or less, which represented approximately 80% of the overall study population, denosumab reduced the risk of bone metastasis or death compared with placebo by 16% (p=.042) and increased bone metastasis-free survival by 6 months-from a median of 22.4 months to a median of 28.4 months.

In an even higher-risk subset of patients with a PSA doubling time of 6 months or less at baseline (representing about 60% of the overall study population), denosumab recipients had a 23% relative reduction in the risk of bone metastasis or death compared with placebo (p=.006) and an increase of 7.2 months in bone metastasis-free survival-from a median of 18.7 months to a median of 25.9 months.

"This trend continued in higher-risk subjects," said Dr. Smith, such that subjects with a PSA doubling time of 4 months or less at baseline (about 40% of the overall study population) who were randomized to denosumab had a 29% reduction in the risk of bone metastasis or death compared with placebo (p=.004) and an increase in bone metastasis-free survival of 7.5 months-from a median of 18.3 months to a median of 25.8 months.

The data confirmed that PSA doubling time is a useful tool to identify patients at greater risk for bone metastasis or death and that denosumab treatment has a robust treatment effect in men at high risk based on a shorter PSA doubling time, he said.

Dr. Smith has a consultant and/or advisory role with Amgen, Inc., Exelixis, Inc., and Novartis. Several of his co-authors have consultant and/or advisory roles, an employment or leadership position, and/or receive honoraria and/or research funding from Amgen.