Denosumab Still in the Running
As I always say: No so fast!
After reviewing safety and efficacy data from 30 clinical studies (12,000+ patients), the FDA Advisory Committee for Reproductive Health Drugs (ACRHD) unanimously recommended approval of denosumab (Prolia) for the treatment of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer, although the panelists suggested that the drug be only used by patients who face the greatest risk of fractures. In addition, , the panel ruled against using the drug as a preventive measure for women with low bone density.
But in a separate 12-3 vote the FDA ACRHD voted against approval for the treatment or prevention of bone loss in women with breast cancer undergoing hormone ablation until additional safety data are available, based on three deaths in the dose-finding trial due new malignancies, which the Committee viewed as at least suggesting some potential for tumor progression in patients with (pre)existing cancer (specific carcinogenicity studies could not be performed, as denosumab is not active in any rodent species).
But in fact, things are not so clear re the issue of safety in breast cancer populations, and it appears the reporting media did not critically review the FDA ACRHD report and findings themselves (which I did). So several things have been missed in the popular media reporting on denosumab.
First, on the very same day as the FDA ACRHD report was published, two of the registration trials, both RCTs, for denosumab were also published in the New England Journal of Medicine / NEJM (early online release). And in 7800+ postmenopausal women there was no increased rate of malignancies, nor of serious infections or most other serious adverse events.
Second, note that the three deaths cited by the ACRHD were among 12,000 treated patients, and that furthermore, it is important to note that despite these, deaths were no more frequent in the denosumab groups versus placebo in any of the trials.
Finally, and most critically, the deaths were exclusively in individuals who received 100-mg dosing, whereas 60 mg was used in all the more robust phase III studies none of which raised any adverse safety signals, and I am absolutely confidant that 60mg will be the recommended dose upon approval, and that Amgen will not even seek approval for the 100mg dosing that the FDA committee has voiced its concern about.
Amazingly, and regrettably, all this was missed in any reporting, popular or professional, so at this juncture, it appears to me that the FDA, which is not obligated to follow any guidance issued by the Advisory Committee for Reproductive Health Drugs (ACRHD), will turn over the safety evaluation of denosumab to the more mature Oncologic Drugs Advisory Committee (ODAC), and given the methodological problems I discussed above that were exhibited in, and hence compromise, the ACRHD report, I still am anticipating positive FDA approval in October.
Breast Cancer Watch