Amgen Inc. will have to rely on the fact that FDA accepts many applications in advanced metastatic disease that rely on less clinically meaningful endpoints than overall survival due to the difficulty of developing treatments when its monoclonal antibody Xgeva (denosumab) comes up for advisory panel review.

The Oncologic Drugs Advisory Committee will examine the company’s proposed indication for men with castrate-resistant prostate cancer at high risk of developing bone metastases when it meets Feb. 8. Filed last June 27, the PDUFA date for this indication is April 26. The drug already is approved as Xgeva for bone problems caused by solid tumors that have metastasized and as Prolia for osteoporosis in postmenopausal women at risk of breaking bones.

A study published online Nov. 16 in Lancet Oncology reported findings that Xgeva extended bone metastasis-free survival and time to first bone metastasis, although not overall survival. The international, placebo-controlled Phase III study involving 1,432 men with castration-resistant prostate cancer also found denosumab was associated with fewer symptomatic bone metastases in these high-risk patients ([A#29111117002]).

September Discussion Provides Clues

ODAC last took up the issue of prostate cancer treatments, although without reference to any specific product, in September, when FDA asked it to discuss whether treatment of patients with non-metastatic castration-resistant prostate cancer represents an unmet medical need, among other issues Also see "Ferraprox Advisory Cmte: Can Risk Management Overcome Safety, Dosing Worries?" - Pink Sheet, 12 September, 2011..

The committee’s discussion then highlights the issues it will face with Xgeva, and hints at the direction the conversation may go regarding claims based on treatment of asymptomatic, radiographic bone metastasis.

“At this point, I think that I would not have difficulty … if a product delays metastasis for a couple of years or for a few years with an acceptable safety profile,” Yang-Min (Max) Ning, a medical officer with FDA's Division of Oncology Products 1, said. “However, I do have a difficulty” with a product that “prolonged or delayed metastasis for a few months with considerable toxicity that does not have any overall survival improvement.”

“I'd just like to clarify here that we do not think delaying or preventing [asymptomatic, radiographic] bone metastasis currently represents a clinical benefit,” Ning said.

In follow-up emails, Ning noted, “As implicated in the FDA briefing document for that meeting, delay in symptomatic metastasis would be clinically important or meaningful. … [But] whether a product that has delayed symptomatic metastasis would receive regulatory approval depends on the demonstrated benefit-risk profile of the product.” He emphasized that these are his individual views and should not be interpreted to represent the division or agency.

Brent Logan, Medical College of Wisconsin, said at the ODAC meeting, that the length of the benefit seen in patients might determine whether a treatment was ultimately worthwhile. “In terms of defining a magnitude of benefit, in terms of something like time to metastasis, metastasis-free survival, as a potential surrogate endpoint, it seems to me that a lot of this hinges on … the longer the duration of time there would be, the longer potential benefit in time to metastasis, in order to better predict for a survival benefit. It's also important to remember that what's considered a potential benefit depends on the toxicity of the intervention.”

“Rather than time to metastasis, it might be better to use metastasis-free survival, because of the potential impact of the intervention, the toxicity, on non-metastasis mortality,” he added.

[Editor’s note: This article has been corrected to clarify a quote by FDA medical officer Ning. He was expressing his personal views about treatments for asymptomatic, radiographic bone metastasis.]

Amgen’s Xgeva For Castration-Resistant Prostate Cancer Faces Panel Review Without Overall Survival Advantage

More from US FDA Performance Tracker

More from Regulatory Trackers