"Show me the benefit" was the mantra Wednesday when an FDA advisory committee critiqued the ability of Amgen Inc.'s Xgeva to prolong the time until bone metastasis in men with castration-resistant prostate cancer (CRPC).

In an evaluation harsher than that of the FDA, the Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 that Xgeva (denosumab) did not demonstrate a favorable risk/benefit for the patient population.

James Kiefert, the patient representative on the panel, cast the sole yes vote, saying he would like to see Xgeva available as a tool in the bag of oncologists who know how to use it.

Panel member Maha Hussain, associate chief for clinical research in the hematology/oncology division at the University of Michigan, countered that if CRPC patients were asked if they wanted to delay bone metastasis, that's a "no brainer." But Xgeva in that indication is not a no-risk benefit, she added, because its benefit has not been quantified.

For a drug to be approved, she said, sponsors must distinguish the meaningful benefits of a drug to patients and show how those benefits offset the costs and side effects. (By law, the FDA can't consider costs in reviewing a drug for approval.)

Responding during the public comment period, Deepak Kapoor, a urologist who is chairman and CEO of Integrated Medical Professionals, pointed out that the cost of therapy isn't the only cost involved. Relating the story of an elderly man with CRPC who was caring for his sick wife, Kapoor reminded the panel of the steep costs that can be involved in managing the complications of a skeletal-related event.

When the patient suffered several fractures, he was confined to a wheelchair and was no longer able to care for his wife. Consequently, she was sent to a nursing home and he had to have care, too, Kapoor said.

From the start, the ODAC panel seemed stacked against Xgeva as none of the members had a specialty in urology. Instead, the members came to the discussion with backgrounds in breast cancer, hematology, lymphoma, gynecologic oncology, radiation oncology, general oncology and statistics. As such, their focus was more on survival benefits rather than time to bone metastasis.

"Oncologists need to see a material [overall survival] benefit to view a drug as worthwhile," Deutsche Bank analyst Robyn Karnauskas said in a note before the meeting. Urologists, on the other hand, value delaying bone metastases as it leads to less pain and better quality of life. (See BioWorld Today, Jan. 7, 2012.)

Although they weren't on the panel, several urologists shared their perspective in limited time slots during the public comment period. They reminded the committee that the median age in the Amgen trial was 74.

"The goal, as we see it, is not simply to live longer but to live better," said Skip Lockwood, CEO and executive vice president of the ZERO Project in Prostate Cancer. He noted that 50 percent to 70 percent of those patients will suffer a skeletal-related event that will profoundly affect their quality of life. Anything that would prevent or delay such events must be given serious consideration, he said.

Cumulative Risks, Endpoints

While the ODAC panel was critical of Amgen's clinical trial to support the expanded use of Xgeva, the FDA called it well designed. The agency's issue wasn't the trial or even the endpoint. Rather, it was the unknown risk of the cumulative use of the drug, as it is already approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

The FDA noted that if Xgeva were approved as a prophylactic, some men could be on it for five to 10 years.

Matthew Smith, the principal investigator for Amgen's trial and a professor at Harvard Medical School, said the idea that those high-risk patients would be on denosumab that long is just wrong. "Unfortunately, they would be dead before 10 years," he added.

Much of the panel's discussion centered on appropriate endpoints, with some members insisting on overall survival as the best endpoint for a cancer drug. But in wrapping up the meeting, committee chairman Wyndham Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, said he didn't want to throw a chilling effect on the field by ruling out other endpoints.

Surrogate endpoints, such as the bone metastasis-free survival that Amgen used, are important and useful, Wilson said, but their magnitude must be more significant and longer than the four-month improvement Xgeva demonstrated.

Despite the lack of ODAC support, Thousand Oaks, Calif.-based Amgen is continuing to build a case for Xgeva's use to delay bone metastasis in the high-risk CRPC group. Following the meeting, Amgen said it hopes to have further discussions with the FDA before the April 26 PDUFA date for the expanded indication. "The development of bone metastases in men with castration-resistant prostate cancer is a clinically significant event, and delaying bone metastases in these men is a clear unmet need with no approved therapies," Amgen said in a statement.

In addition to Xgeva, Amgen markets Prolia, a smaller dosage form of denosumab approved to increase bone mass in postmenopausal osteoporosis and in breast and prostate cancer patients. The company recently reported $351 million in 2011 sales for Xgeva and $203 million for Prolia. (See BioWorld Today, Oct. 26, 2011 .)

Amgen (NASDAQ:AMGN) didn't suspend trading during the ODAC meeting. Its shares were down $1.11, closing at $68.06 Wednesday.