The Food and Drug Administration questions whether an additional indication for denosumab to delay bone metastases in men with castrate-resistant prostate cancer who are at high risk for such metastases would provide benefit beyond that seen with the current use of denosumab to prevent skeletal-related events in solid tumors metastatic to bone.
The pivotal trial (20050147) for the castrate-resistant prostate cancer (CRPC) indication was not designed to demonstrate that administering "denosumab prior to the development of osseous metastases would add to the clinical benefit already established for denosumab" in preventing skeletal-related events (SREs) in metastatic disease, the FDA says in briefing materials for a Feb. 8 Oncologic Drugs Advisory Committee meeting.
The indication for the drug (marketed as Xgeva by Amgen Inc.) to be discussed by the panel is "for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases. Xgeva prolongs bone metastasis–free survival by reducing the risk of developing bone metastases." The FDA approved Xgeva for the prevention of SREs in late 2010.
To find clinically meaningful benefit for the new indication, a study would have to compare the clinical benefits of continuous denosumab treatment of the CRPC target population with the benefits of treatment only after bone metastasis occurs, the FDA suggests.
In such a trial, the agency notes, an appropriate end point would be designed to assess a meaningful clinical benefit, such as prevention of SREs.
"If denosumab administered to patients with CRPC (at high risk for bone metastases) does not add to the benefit observed in patients who have metastatic disease, then patients will only be exposed to the increased risks of the drug," the agency points out.
In its briefing materials, Amgen says the benefit of the bone metastasis–free survival (BMFS) indication "is complementary to and consistent" with the benefit of preventing SREs in metastatic CRPC. It "allows physicians the opportunity to intervene earlier in the prostate cancer treatment continuum to prevent the significant morbidity associated with bone metastases," the company contends.
More Risk With Longer Exposure
The FDA expressed concern that treatment to delay bone metastasis would extend patient exposure to denosumab and increase the risk for osteonecrosis of the jaw (ONJ), a major safety concern with the biologic.
As confirmed by an adjudication committee, ONJ occurred in 33 (or 4.6%) of the denosumab-treated patients and in none of the placebo patients during the primary analysis phase of study 20050147. In the follow-up of patients through the extended blinded treatment phase, overall incidence of ONJ was 5.4% in the denosumab-treated patients.
These figures are higher than those in study 20050103, a prostate cancer trial that supported Xgeva’s indication for SRE prevention. Median duration of exposure in the two trials was 19.3 months in 20050147 vs. 11.9 months in 20050103.
The 20050147 results "suggest the possibility that the risk of ONJ increases with increasing exposure to denosumab as Xgeva, and that continued long-term exposure may increase the ONJ rate to a level that off-sets the risk/benefit profile for the SRE indication in patients with prostate cancer," the FDA points out.
A 120-day safety update reported another six patients with ONJ events among the 100 patients in the denosumab arm of the open-label extension phase of study 20050147.
What’s An Appropriate Surrogate for Benefit?
Use of bone metastasis–free survival as the basis for drug approval or a labeling claim would set a precedent, and the FDA will ask the panel to weigh in on whether the end point is either a surrogate for clinical benefit or a direct clinical benefit.
The agency’s opinion is that "available data with denosumab do not support a conclusion that BMFS is a surrogate [end point] for OS [overall survival]".
The two prostate cancer trials did not show a treatment effect for denosumab on overall survival or on progression-free survival, and there was no improvement in PSA over time vs. placebo in the pivotal trial for BMFS, the FDA says.
"Ultimately, an application with BMFS as a primary end point would be strengthened by findings that also demonstrate an improvement in the time to SREs or a substantial improvement in quality of life (especially related to clinically relevant pain scores)," the FDA says.
Is Magnitude of Effect Large Enough?
Even if BMSF were considered a meaningful benefit, the FDA will ask the panel to consider whether the magnitude of BMFS seen in study 20050147 is sufficient to conclude that Xgeva has a favorable risk/benefit profile in CRPC patients who are at high risk for bone metastases.