NEW ORLEANSA 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
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
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 =
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
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).