WASHINGTON – What do a biostatistician, pediatric oncologist, gynecology oncologist and hematology oncologist have in common?

They're all serving on the advisory committee being convened Wednesday to weigh in on the risks/benefits of Amgen Inc.'s Xgeva in reducing the risk of bone metastasis in men with castration-resistant prostate cancer (CRPC).

What's missing, at least on the roster the FDA put out Monday, is anyone with a specialty in urology.

"While this may indicate the FDA's intention to gather a broader view of this novel indication in cancer drugs, we believe urology/oncologists to be key target specialists for Xgeva, warranting their representation," Jefferies analyst Eun Yang said in a note.

The absence of urologists may not be good news for Thousand Oaks, Calif.-based Amgen, as it could make a positive committee vote more difficult, Deutsche Bank analyst Robyn Karnauskas said.

"Oncologists need to see a material [overall survival] benefit to view a drug as worthwhile," Karnauskas explained in a note, whereas urologists value delaying bone metastases as it leads to less pain and better quality of life.

Endpoints could be a point of contention at this week's meeting of the Oncologic Drugs Advisory Committee (ODAC). While Xgeva (denosumab) demonstrated a median 4.3-month improvement in bone metastasis-free survival (BMFS), it didn't result in an improvement in overall survival or progression-free survival (PFS), the FDA said in briefing documents.

Denosumab is the first drug to delay the appearance of bone metastases in a randomized, placebo-controlled trial in patients with nonmetastatic CRPC, but whether ODAC thinks that's enough for approval remains to be seen.

In the past, ODAC members have split on appropriate endpoints for CRPC.

Just last September, some members indicated overall survival was the appropriate endpoint, but others supported the use of PFS or BMFS. However, several of those supporting PFS or BMFS said the benefit effect should be greater than six months, with some pushing for at least a year. (See BioWorld Today, Sept. 16, 2011.)

At the September meeting, urologists voiced their support for using bone metastases as an endpoint.

"Bone metastases-free survival is a valid and robust endpoint for clinical studies and is a clinically useful objective to aim for in our management of patients with prostate cancer," Fred Saad, a professor and chairman of the urology division at the University of Montreal Hospital Center, said in a statement submitted for the meeting.

He pointed out that the primary endpoint of the large, randomized RADICALS trial being conducted in Canada and the UK has been changed from cancer-specific survival to bone metastases-free survival because of the significance related to the appearance of bone metastases.

Amgen used BMFS as the primary endpoint in its randomized, double-blind, placebo-controlled trial in 1,432 men with CRPC considered at high risk for bone metastases. That study, which is being used to support the supplemental biologic license application for Xgeva, demonstrated a median BMFS of 29.5 months for the denosumab arm and 25.2 months for the placebo arm.

The median time to first bone metastasis was 33.2 months for denosumab compared with 29.5 months for placebo. But median survival was 43.9 months for denosumab vs. 44.8 months for placebo.

"A post-hoc exploratory analysis of time to symptomatic bone metastasis, which may be considered a more relevant measure of clinical benefit in this setting, is of limited value due to missing data since most patients were not followed until they experienced the first symptomatic metastasis," the FDA said.

In addition to the endpoints, the agency raised concerns about adverse events observed in the trial. A 5 percent per-patient incidence of osteonecrosis of the jaw (ONJ) in the denosumab arm was higher than that seen in trials to support Xgeva's initial approval for the prevention of skeletal-related events in patients with bone metastases from solid tumors, the FDA said.

That's worrisome, the agency said, because the cumulative risk of ONJ for men who could be treated with denosumab across the continuum of prostate cancer disease states is not known.

The FDA also questioned the benefit of using denosumab as a preventive drug for bone metastases vs. treating at the time of the development of an osseous metastasis.

The agency's concerns were not surprising, given the comments made at the September 2011 ODAC meeting. Several analysts expect the panel to be more positive than the FDA, in light of the drug's benefit in BMFS and the lack of current treatment options.

"Despite the negative tone of the documents, we continue to see a reasonable probability of a positive AdCom recommendation, although we do not expect the panel's decision to be unanimous," Openheimer analyst Brett Holley said in a note.

Yang agreed that approval is likely. But even if Xgeva, which has an April 26 PDUFA date for the CRPC indication, doesn't get the expanded label, Yang said it would have a limited impact on Amgen's stock (NASDAQ:AMGN), which closed Monday at $69.12, down 16 cents.

CRS: Biosimilar Competition a Ways off

Biopharma's rush toward biosimilars is not likely to lead to much biologic competition and cheaper prices in the foreseeable future, according to a new Congressional Research Service (CRS) report.

While several companies already are meeting with the FDA to get the regulatory process rolling on their biosimilars, a number of scientific and legal issues related to follow-on biologics will likely play out in the courts and the FDA for many years to come, the report said. (See BioWorld Today, Feb. 6, 2012.)

The CRS also predicted that it may take some time for the biologics industry to develop a working familiarity and appropriate strategies within the Biologics Price Competition and Innovation Act framework.

"As a result, marketplace availability of significant numbers of follow-on biologics may not be a short-term proposition," it said.