On Wed, Feb 8, 2012 the FDA Oncology Advisory Committee will discuss Amgen‘s supplement to their approved BLA for XGEVA (denosumab) for treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases.
This Advisory Committee discussion and the ultimate FDA approval decision comes down once again to the basic benefit risk decision. On the benefit side, treatment with denosumab did not result in an improvement in overall survival or progression free survival but it did improve bone metastasis-free survival (BMFS) and time to first bone metastasis, both by about 4 months. On the risk side, the incidence of osteonecrosis of the jaw with denosumab increased by about 5%. So, the basic benefit risk question is does the 4 month improvement outweigh the 5% increased risk?
The other significant question raised by the FDA appears to boil down to whether treatment with denosumab in this setting offers any advantage versus “prevention of skeletal related events in patients with solid tumors metastatic to bone”, the approved indication.
The FDA review appears to be on the negative side of neutral. While the company met the primary endpoint, the FDA review points out that at meetings with the company, the FDA noted that “overall survival, patterns of metastases, and the development of symptomatic metastases will be important review issues”. There was no advantage in overall survival. Also, of significant note is the statement in the FDA review that the study was not conducted under a Special Protocol Assessment, meaning there is no “contract” for approval just because the primary endpoint (improvement in BMFS) was met.