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The Cancer Letter Inc.
P.O. Box 9905
Washington, D.C. 20016
Tel: 202-362-1809
Fax: 202-595-1310
publication date: Feb 17, 2012
The FDA Oncologic Drugs Advisory Committee voted 12-1 against 
approval of the Amgen Inc. drug Xgeva (denosumab) for the treatment 
of men with castrate-resistant prostate cancer who are at high risk of 
developing bone metastases.
ODAC’s recommendation at the Feb. 8 meeting is consistent with 
the views it expressed about the proposed indication at a meeting last 
September (The Cancer Letter, Sept. 23, 2011). 
The committee’s recommendation on this Supplemental Biologics
License Application also appears to constitute clinical advice on the validity 
of the indication of “castrate-resistant non-metastatic prostate cancer.” 
This indication reflects a cascade of medical services which begins 
when men are found to have prostate cancer after screening with the 
prostate-specific antigen. After this, the patients receive surgery. After 
the PSA begins to rise, the patients receive hormonal treatments. When 
the PSA level starts to climb despite these treatments, even in the absence 
of clinical signs of disease, the patients can be classified as castrate-resistant 
and non-metastatic.
This proposed indication was ushered into existence by the use of PSA, 
which isn’t approved for population-wide screening, and by the widespread use 
of androgen deprivation therapy to treat disease early in its course.  (Hormones 
are approved for end-stage disease.) 
The committee’s decisions on Xgeva can affect a class of drugs that are now 
in the development pipeline. 
Also, the application raises questions about the trial designs for therapies 
that would be used for “maintenance.” The agency routinely approves applications
based on placebo-controlled trials in the maintenance setting. However, an 
alternative trial design would be to compare the use of the drug in the maintenance 
phase, compared to starting the drug at the time of documented progression, 
agency officials say.
While discussion of the validity of this indication dominated the 
committee’s meeting last September, the Feb. 8 ODAC meeting focused 
exclusively on the data Amgen provided in support of the application. 
Approval, which at this point appears unlikely, would have moved 
the use of Xgeva, a RANK ligand inhibitor, to an earlier point in the disease.
Xgeva is approved for the prevention of skeletal-related events in patients 
with solid tumors metastatic to bone, including prostate cancer.  It is also 
approved under the name Prolia, for postmenopausal women with osteoporosis 
at high risk for fracture, and as a treatment to increase bone mass in men at 
high risk for fracture receiving androgen deprivation therapy for non-metastatic 
prostate cancer.
Amgen wanted to deliver Xgeva in a preventive, prophylactic setting, 
and the committee had to decide whether an earlier exposure was better than 
using the drug in its currently approved indications, the prevention of 
skeletal-related events in metastatic patients. 
Moreover, the committee had to grapple with the question of the 
magnitude of benefit demonstrated in the application. If approved for this 
indication, Amgen could have won a trifecta: extending from the initiation of 
denosumab (as Prolia) to prevent bone loss from ADT, through the prevention 
of bone metastases in patients who are castrate-resistant, and continuing in 
the indication to prevent skeleton-related events in men with known bone 
metastases. The use of the drug could last for many years, starting with the 
initiation of ADT therapy through death. 

Amgen’s Case for Approval
The company focused the trial’s population of men with no bone or other 
distant metastases (excluding previous untreated local-regional disease and 
metastatic nodal disease), who had received hormonal treatments and whose 
PSA level was above 8 ng/mL or had doubled in less than 10 months.
Patients were randomized into two arms, receiving either 120 mg of 
denosumab every four weeks, or placebo.
The primary endpoint—bone-metastasis-free survival—was chosen 
because of the prophylactic nature of the trial. Overall survival was a secondary 
endpoint. Patients were taken off therapy following first bone metastases 
or high toxicity. Patients underwent a bone scan every 16 weeks, with 
skeletal metastases confirmed by X-ray, CT or MRI.
In the treatment arm, denosumab increased time to bone metastases 
by 4.2 months (HR=0.85 [95% CI: 0.73, 0.98]).
Overall survival was similar compared to placebo, with a hazard ratio of 
1.01 (95% CI: 0.85, 1.20; p=0.91), with median survival 43.9 months (40.1 NE) 
on denosumab, and 44.9 (40.0 NE) on placebo.
Median progression-free survival was 21.7 months on denosumab, and 
19.3 on placebo.
With this information, FDA sought the committee’s advice on one question: 
“Has denosumab demonstrated a favorable risk/benefit evaluation for the 
treatment of castrate resistant prostate cancer at high risk for metastases?”

Copyright (c) 2014 The Cancer Letter Inc.