Denosumab superior to Zometa in delay of complications in Stage IVs due to bone mets

[Lani]

Amgen (Nasdaq: AMGN) announced detailed results from a Phase 3, head-to-head trial evaluating denosumab versus Zometa(R) (zoledronic acid) in the treatment of bone metastases in 2,046 patients with advanced breast cancer that met its primary and secondary endpoints and demonstrated superior efficacy compared to Zometa. These results were presented during the Presidential Session at the 2009 ECCO 15 - ESMO 34 European Multidisciplinary Congress in Berlin, Germany (Abstract Number 2LBA).

Denosumab administered subcutaneously demonstrated superiority for both delaying the time to the first on-study skeletal related events (SREs) (fracture, radiation to bone, surgery to bone, or spinal cord compression) (hazard ratio 0.82, 95 percent CI: 0.71, 0.95), and delaying the time to first-and-subsequent SREs (hazard ratio 0.77, 95 percent CI:0.66, 0.89). Both results were statistically significant in this 34 month study. The median time to first on-study SRE was not reached for denosumab and therefore could not be estimated. The median time to first on-study SRE was 26.5 months for Zometa, the current standard of care.

"Up to 80 percent of patients with advanced breast cancer will develop bone metastases that are often associated with severe and painful bone complications, which are a serious concern for both patients and physicians," said Alison Stopeck, M.D., associate professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, AZ, United States of America. "Denosumab was superior to Zometa in preventing skeletal related events and delayed worsening of bone pain. In addition, denosumab also presented some potential tolerability advantages for many patients, including a lower incidence of renal toxicity and acute phase reactions, combined with the convenience of a monthly subcutaneous injection. Denosumab would be a welcome new treatment option for advanced breast cancer patients."

Denosumab also delayed the median time to first on-study SRE or hypercalcemia of malignancy (HCM) compared to Zometa (hazard ratio 0.82, 95 percent CI: 0.70, 0.95; p=0.007). The median time to first on-study SRE or HCM was not reached for denosumab and therefore could not be estimated. The median time to first on-study SRE or HCM was 25.2 months for Zometa.

Bone pain can dominate the daily lives of patients with metastatic disease involving bone and is often characterized as severe or intolerable.(1) In a pre-specified exploratory analysis, patients on the denosumab arm reported worsening of pain later than those on the Zometa arm (88 days versus 64 days, respectively; hazard ratio 0.87, 95 percent CI: 0.79, 0.97; p=0.009).

Overall, the incidence of adverse events (96 percent denosumab, 97 percent Zometa) and serious adverse events (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa. Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; p=0.50) and time to cancer progression (hazard ratio 0.99, 95 percent CI: 0.89, 1.11; p=0.90) was balanced between treatment arms.

Detailed data from another Phase 3, head-to-head trial evaluating denosumab versus Zometa was presented yesterday (Abstract #20LBA). In this study of 1,776 advanced cancer patients with solid tumors (not including breast and prostate cancer) or multiple myeloma, denosumab met its primary endpoint and demonstrated non-inferiority compared to Zometa in the treatment of bone metastases.

Study Design

This was an international, Phase 3, randomized, double-blind study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced breast cancer. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks as per the label instructions.

In clinical trials testing new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, the need for radiation to bone, the need for bone surgery, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa.

The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first, on-study SRE in patients with advanced breast cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first, on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.