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
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
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?”