Amgen announced that they have published the results from their Phase 3 trial (the ‘147 study) that evaluated XGEVA® (denosumab) for use in preventing or delaying the onset of bone metastases in men with non-metastatic castration-resistant prostate cancer (CRPC). The results were published in The Lancet.

The study found XGEVA significantly prolonged bone metastasis-free survival, delayed time to bone metastasis and reduced the risk of symptomatic bone metastases. This study is the first to demonstrate that targeting the bone micro-environment prevents bone metastasis in men with prostate cancer.

“The prevention of bone metastases is a major unmet medical need for men with castration-resistant prostate cancer. Bone metastases are a significant concern for these patients who have historically had poor outcomes,” Matthew Smith, M.D., Ph.D., professor of medicine and the director of Genitourinary Oncology at Massachusetts General Hospital Cancer Center. “The more than four-month increase in bone metastasis-free survival with XGEVA treatment is a clinically significant finding that has the potential to improve the management of men living with prostate cancer.”

Based on the results of this study, Amgen filed a supplemental Biologics License Application (sBLA) to expand the indication for XGEVA to treat men with CRPC to reduce the risk of developing bone metastases. The U.S. Food and Drug Administration (FDA) has set April 26, 2012 as the targeted Prescription Drug User Fee Act (PDUFA) action date for the sBLA. If approved, XGEVA would be the first-and-only therapy licensed to prevent or delay the spread of cancer to the bone.

In the ‘147 study, XGEVA significantly improved median bone metastasis-free survival by:

(A) 4.2 months, a risk reduction of 15 percent, compared with placebo (29.5 versus 25.2 months, respectively; hazard ratio (HR) 0.85; 95 percent CI: 0.73, 0.98; p=0.028).

(B) XGEVA significantly delayed the time to first bone metastases by 3.7 months compared with placebo (HR 0.84; 95 percent CI: 0.71, 0.98; p=0.032; risk reduction of 16 percent).

(C) XGEVA also reduced the risk of bone metastases that were symptomatic by 33 percent (HR 0.67; 95 percent CI: 0.49, 0.92; p=0.01).

(D) Overall survival was similar between groups (HR 1.01; 95 percent CI: 0.85, 1.20; p=0.91).

(E) The study design required that patients discontinue XGEVA following development of bone metastasis so that they could receive standard approved treatment for prevention of skeletal-related events (SREs), therefore, the potential to measure a positive impact on survival was limited.

In the trial the adverse events and serious adverse events were relatively similar between the XGEVA and placebo arms. They were:

(A)Hypocalcemia and osteonecrosis of the jaw (ONJ) were reported with increased frequencies in the XGEVA treated patients.

(B)The yearly rate of ONJ in the XGEVA arm was similar to prior XGEVA trial results.

(C) Back pain was the most common adverse event reported in the XGEVA arm of the trial.

Study ‘147 was a randomized, placebo-controlled, multi-center Phase 3 study of 1,432 men with hormone-refractory (castration-resistant) prostate cancer who had no bone metastases at baseline but were at increased risk of developing them based on their prostate specific antigen (PSA). The study compared the treatment effect of XGEVA to placebo in prolonging bone metastasis-free survival. The primary endpoint of the trial was time to first occurrence of bone metastases or death from any cause with secondary endpoints including time to first occurrence of bone metastases (excluding death) and overall survival.

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Joel T Nowak, M.A., M.S.W.