Continued Benefit at 2 Years With Zometa in Advanced Ca

NEW ORLEANS—A new analysis of long-term zoledronic acid (Zometa) therapy in advanced prostate cancer patients with bone metastases showed significant ongoing benefit, Fred Saad, MD, reported at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 4575). A second analysis of the data showed that bisphosphonate therapy offers clinical benefit in these patients regardless of whether they had a skeletal-related event (SRE) prior to entry into the study (abstract 4576).

Bone metastases, which occur in 65% to 75% of advanced prostate cancer patients, can lead to skeletal complications, said Dr. Saad, of the Centre Hospitalier de l’Universite de Montreal. Median survival after bone metastases are diagnosed is 2 to 3 years. Dr. Saad and his colleagues had earlier reported that 4 mg of zoledronic acid every 3 weeks for 15 months significantly reduced the incidence of SREs, compared with placebo, in this population (J Natl Cancer Inst 94:1458-1468, 2002). Longer-term therapy, he said, may be needed to prevent SREs and to maintain quality of life.

Of 147 patients completing the 15-month core phase of the trial, 133 elected to enter a 9-month extension phase. Included patients received either zoledronic acid (15-minute infusion) every 3 weeks (n = 82) or placebo (n = 65). The primary endpoint was the proportion of patients with one or more SREs (defined as pathologic fracture, spinal cord compression, radiation therapy to bone, surgery to bone, and change to chemotherapy to treat bone pain).

In the 9-month extension, SREs were experienced by 19% of patients in the zoledronic acid group and by 38% of patients in the placebo group (P = .017), a 50% relative reduction in the extended-treatment group. In the first 15 months of the trial, the percentages had been 33% and 44%, respectively (P = .021).

Furthermore, in the 9-month extension, the reduction in risk of developing an SRE was 53% with zoledronic acid, compared with placebo (P = .022). In the first 15 months of the study, the risk reduction was 36% (P = .004).

Mean skeletal morbidity rates (SMRs) during the extension were 0.42 SREs/year for zoledronic acid vs 0.88 SREs/year for placebo (P = .016). The SMRs for the first 15 months had been 0.80 and 1.49, respectively (P = .006).

Dr. Saad noted that the high rate of SREs in the placebo group in months 15 to 24 illustrates the continued SRE risk in this population. He concluded that extension of zoledronic acid produced an even greater benefit than that seen in the core phase of the trial, suggesting that there is no decrease in efficacy associated with long-term use of the agent.

Joseph L. Chin, MD, London Health Sciences Centre, London, Ontario, Canada, reported a further analysis of the same study in which patients were stratified retrospectively according to history of an SRE (as defined above, plus hypercalcemia of malignancy) before study entry. Approximately one-third of patients had experienced an SRE before entry into the study.

Andersen-Gill multiple event analysis, a method that takes several factors into account to afford a sensitive measure of skeletal complication risk, demonstrated that zoledronic acid significantly reduced SRE risk in both subsets of patients in months 1 to 24 of the study. With zoledronic acid, the relative risk (RR) of developing an SRE was reduced by 33% in those with no prior SRE (P = .027) and by 40% in those with a prior SRE (P = .028), with an overall RR reduction of 36% (P = .002).

Dr. Chin noted also that median time to first on-study SRE trended in favor of the zoledronic acid group in those with a prior SRE (361 days vs 258 days, P = .066) and in those without a prior SRE (499 days vs 337 days, P = .065).

He concluded that 4 mg of zoledronic acid every 3 weeks reduced the incidence of skeletal complications regardless of patient history of SREs before study entry. In both groups, the proportion of patients who experienced an SRE on-study was reduced and the time to first SRE was extended. Results of both studies were published in the June 2, 2004, issue of the Journal of the National Cancer Institute (96:879-882, 2004).