According to a media release, issued late yesterday by Amgen, treatment with denosumab can significantly improve bone metastasis-free survival compared to treatment with a placebo in men with castrate-resistant prostate cancer (CRPC), a rising PSA, but no evidence of bone metastases.
The data available from Amgen at the present time are preliminary, “top-line” results. A company representative has stated that, “We look forward to presenting these landmark data at an upcoming medical conference.” One might reasonably expect this to occur at the Genitourinary Cancers Symposium scheduled for February in Orlando.
The background information about the so-called ‘147 study is available on the ClinicalTrials.gov web site. Basically, this study randomized 1,432 men with CRPC to treatment with denosumab (120 mg s.c. every 4 weeks) or a placebo. To be eligible for the trial, in addition to having CRPC, patients had to meet the following criteria:
- A total testosterone level of 50 ng/dl or less
- Three consecutive increases in PSA levels, with each PSA value taken at least 2 weeks after the preceding level, such that each consecutive PSA value was at least 1.0 ng/ml higher than the preceding value
- A significant risk for development of bone metastasis (i.e., a PSA level ≥ 8.0 ng/ml no more than 3 months before randomization or a PSA doubling time ≤ 10.0 months)
- No evidence of radiographically detectable bone metastasis before or at the time of study enrollment
- No evidence of metastatic involvement of other distant organs (with the exception of lymph node metastases in any region)
- No prior or current treatment with an intravenous bisphosphonate (such as zoledronic acid)
The fundamental results of the study, as announced by Amgen yesterday, are as follows:
- Denosumab therapy significantly improved average (median) bone metastasis-free survival by 4.2 months (hazard ratio [HR]=0.85) compared to the placebo
- Denosumab therapy also significantly improved time to the first documentable evidence of bone metastases (again compared to the placebo).
- There was no difference between the overall survival of patients treated with denosumab and those treated with placebo.
- Overall rates of adverse events and serious adverse events were generally similar between patients in the denosumab and placebo treatment groups.
- Hypocalcemia and osteonecrosis of the jaw (ONJ) were observed more often in the denosumab study arm.
- The annual incidence of ONJ in the denosumab treatment arm was similar to that observed in earlier studies of denosumab.
Denosumab (Xgeva™) was approved by the U.S. Food & Drug Administration (FDA) last month for the prevention of skeletal-related events (SREs) in patients with bone metastasis associated with solid tumors like prostate cancer. We can reasonably expect that Amgen will try to expand the indication for Xgeva based on these new data. The critical question, however, is going to be whether physicians decide that denosumab is a better option than zoledronic acid for the delay of metastasis and the prevention of SREs. It may take a while to know the answer to that question.