The U.S. Food and Drug Administration (FDA) has questioned the value of denosumab (Xgeva®) as an agent capable of delaying the onset of metastatic disease to bone in men with progressive, castration-resistant prostate cancer.
An FDA Advisory Committee will meet on Wednesday this week to discuss the application by Amgen for approval of denosumab as an agent that can be used to prevent the onset of boney metastasis. Earlier today, the FDA issued a detailed “briefing document” that asks tough questions about the value of denosumab in the proposed indication.
The executive summary of the briefing document makes the following key points:
- The application seeks approval of denosumab for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases, based on the results of a single, large, double-blind, randomized, placebo-controlled clinical trial.
- Patients enrolled into this trial were not required to have no evidence of disease (NED); patients with locally progressive disease were eligible, as were patients with metastases to any lymph node, and 55 percent of the patients enrolled in the trial had received no prior local treatment for prostate cancer.
- The FDA has previously advised Amgen that — although the overall design of this study was acceptable — “overall survival, patterns of metastases, and the development of symptomatic metastases” would be important review issues.
- To be eligible for entry into this trial (i.e., to be defined as being at high risk for development of bone metastasis), patients had to meet one or both of two criteria: a PSA level ≥ 8 ng/ml and/or a PSA doubling time ≤ 10 months.
- Final analysis of the study data showed that
- The median time to bone metastasis-free survival (BMFS) was 29.5 months for men in the denosumab arm and 25.2 months for men in the the placebo arm (hazard ratio [HR] = 0.85).
- The median time to first bone metastasis was 33.2 months for men in the denosumab arm and 29.5 months for men in the placebo arm (HR = 0.84).
- Median overall survival was 43.9 months for men in the denosumab arm and 44.8 months for men in the placebo arm (HR = 1.01).
- Treatment with denosumab did not result in an improvement in either overall survival or progression-free survival.
- Most patients in the trial were not followed until they experienced their first symptomatic metastasis.
- The overall incidence of osteonecrosis of the jaw (ONJ) in the denosumab-treated men was about 5 percent per patient, which is higher than the incidence of ONJ observed in trials supporting the approved indication of denosumab (for prevention of skeletal-related events in patients with solid tumors metastatic to bone).
There are clearly serious questions about whether denosumab should or should not be approved for this proposed indication. It is for exactly this reason that the FDA holds advisory committee meetings — to allow the independent advisory board members to hear directly from both the sponsor of the proposed drug use (Amgen in this case) and the FDA’s own reviewers of the data. The independent advisory committees sometimes agree with the company and recommend approval, and sometimes they agree with the FDA’s in-house reviewers and recommend non-approval. The final FDA decision most commonly does, in fact, follow the recommendations of its advisory committees under such circumstances (although there have been well known exceptions to this).
The “New” Prostate Cancer InfoLink suspects that in this case, the advisory committee is not going to recommend approval of denosumab for this indication. If the time to BMFS had been more like 36 months in the denosumab arm of the trial (a really clinically significant difference), or there had been fewer occurrences of ONJ, or there had been any strong suggestion that early use of denosumab really did lead to an overall survival benefit, the outcome would be much more likely to have led to an approval of denosumab for this indication … but one never knows what might happen at these meetings. A single member of the advisory group can sometimes sway the panel, or the panel may feel that the FDA is over-emphasizing the risks associated with the use of this product. We’ll just have to wait and see what happens on Wednesday.