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12:00 AM
 | 
Feb 13, 2012
 |  BioCentury  |  Regulation

Waiting for Xgeva

Amgen likely needs new trial of Xgeva to prevent bone mets in prostate cancer

FDA commentary and panel members' votes at last week's review of Xgeva denosumab from Amgen Inc. make it clear companies working in pre-metastatic CRPC will be held to standards first discussed publicly at a September 2011 panel, regardless of when their trials began.

FDA's Oncologic Drugs Advisory Committee voted 12-1 that Xgeva has not demonstrated a favorable benefit-risk profile for treating pre-metastatic castration-resistant prostate cancer because Amgen did not provide data showing that treatment before metastasis provides a greater benefit than waiting to treat until after metastases appear. Xgeva is approved for the latter indication.

In addition, while Xgeva is the first drug ever to significantly increase bone metastasis-free survival (BMFS) in CRPC, the 4.2-month difference vs. placebo fell short of ODAC's September recommendation that trials using the endpoint show at least a six-month delay (see BioCentury, Sept. 19, 2011).

Unconvinced of the drug's benefit, ODAC members thus gave more weight to safety concerns related to the incidence of osteonecrosis of the jaw (ONJ), which increased with duration of treatment in Amgen's trial.

The panel outcome might have been different had Amgen followed patients longer or been more thorough in its study of quality of life endpoints such as time to first symptomatic metastasis.

It also might have been different had the panel included more urologists, who treat the majority of pre-metastatic CRPC patients. Before and after the panel, many of these doctors told BioCentury they have no doubt that a 4.2-month increase in BMFS translates to a meaningful clinical benefit.

If the agency agrees with the panel's vote, the most likely scenario is that Amgen will need to perform another trial to determine when patients should begin treatment with Xgeva.

"The question isn't, is this drug effective? The question is a matter of timing. Is it safer and equally effective to give it at the time that metastatic disease to the bone is found or is it better to give it in a prophylactic setting?" said ODAC Chairman Wyndham Wilson, who is chief of the lymphoma therapeutics section at the National Cancer Institute.

Timing is everything

The September ODAC panel was the first time FDA engaged in public discussion about endpoints and trial designs for non-metastatic CRPC, by which time Xgeva was already under review.

At that meeting, for agents already approved to treat metastatic CRPC, the agency proposed a trial design in which patients would be randomized to either immediate treatment with the agent or observation. Upon progression in the immediate treatment arm, the patient would be taken off the drug and followed for survival. In the late treatment arm, the...

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