Impact of denosumab on bone metastasis-free survival

A presentation at the American Urological Association annual meeting in Washington a few days ago provided data that treatment with denosumab (Xgeva) delayed the onset of bone metastasis by 4.2 months compared to treatment with a placebo in men with high-risk, non-metastatic, castration-resistant prostate cancer. However, it should be immediately pointed out that the data from the same presentation also showed that treatment with denosumab had no significant impact on the patients’ overall survival.

The presentation by Dr. Matt Smith of Massachusetts General Hospital and Harvard Medical School raises interesting questions about the value of long-term treatment with denosumab (which is already approved for the prevention of skeletal-related events such as fractures) in men being treated with androgen deprivation therapy (ADT):

The details of the protocol for the Phase III clinical trial that provided these data are available on the web site, and they are worth reading with care. All patients in this study had to have had an orchiectomy or they had to have started and stayed on continuous ADT months at least 6 months prior to being enrolled into the study. They also had to have met carefully selected criteria demonstrating  that they were castration resistant and at high risk for further progression. These were definitely men with high-risk, non-metastatic disease. However, it appears that these patients’ other potential forms of therapy were unrestricted, so we don’t know (yet) how many of them may also have been simultaneously participating in trials of drugs like abiraterone, cabazitaxel, and others. In fact we may never know which of these patients actually received such other drugs while participating in the denosumab trial.

The following study data have been extracted from a media release issued by Amgen on May 17:

  • The results of the multi-center, randomized Phase III trial were based on 1,432 patients. (The media release does not tell us how many patients were randomized to each arm of the study, but it was probably about 50:50.)
  • Median bone metastasis-free survival was
    • 29.5 months in patients treated with denosumab
    • 25.2 months in patients treated with placebo
  • The improvement in bone metastasis-free survival was 4.2 months, which represents
    • An absolute risk reduction of 15 percent compared with placebo
    • A hazard ratio (HR) of 0.85
  • Time to first bone metastases was delayed by 3.7 months in men receiving denosumab compared with placebo, which represents
    • An absolute risk reduction of 16 percent
    • HR = 0.84
  • The risk for symptomatic bone metastases was reduced by 33 percent (HR = 0.67)
  • Overall survival was similar between groups (HR = 1.01).
  • Progression-free survival was not significantly different between the two groups either (HR = 0.89).
  • “Adverse events and serious adverse events were relatively similar” between patients in the two arms of the trial.
  • “Hypocalcemia and osteonecrosis of the jaw (ONJ) were reported with increased frequencies” in the patients treated with denosumab.
  • “Back pain was the most common adverse event reported” among patients treated with denosumab.

It is probably a safe bet that the patients in the denosumab arm of the trial also had fewer skeletal-related events than the patients being treated with a placebo, although the study has not reported data on this item (if such data were being collected).

The Amgen media release makes no statement about this, but we assume that Amgen either has already submitted or soon will submit an application to the U.S. Food & Drug Administration requesting permission to market denosumab for delay in the onset of bone metastasis in men with non-metastatic prostate cancer who are being treated with ADT. The first question will be whether the FDA is willing to grant such a broad approval, or will restrict the approval to the subset of men actually studied in the current trial — i.e., those with high-risk, non-metastatic, castration-resistant disease.

Those with an economic bent may want to think about the monthly cost of treatment for a man with non-metastatic, castration-resistant disease — with an LHRH agonist, docetaxel-based chemotherapy (or abiraterone acetate), and denosumab (quite apart from any other needed mediations). The cost of “the best” treatment of advanced forms of prostate cancer is starting to rise significantly.

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