No Benefit of Early Zoledronic Acid in Reducing Skeletal-Related Events in Castration-Sensitive Prostate Cancer With Bone Metastases
As reported in the Journal of Clinical Oncology by Smith et al, the double-blind phase III Cancer and Leukemia Group B (CALGB) 9020/Alliance trial assessed the effect of early initiation of zoledronic acid in reducing risk of skeletal-related events in men with castration-sensitive prostate cancer. There was no reduction in time to first skeletal-related event for zoledronic acid vs placebo.
Study Details
In the trial, 645 men with castration-sensitive prostate cancer and bone metastases who had androgen-deprivation therapy initiated within 6 months of study entry were randomly assigned between January 2004 and May 2012 to receive zoledronic acid at 4 mg intravenously every 4 weeks (n = 323) or placebo (n = 322). All patients received open-label zoledronic acid after progression to castration-resistant disease.
The primary endpoint was time to first skeletal-related event, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer, with analysis in the intention-to-treat population. The target accrual was 680 patients, with primary analysis planned after 470 skeletal-related events.
The study was closed to accrual on June 1, 2012, when the corporate supporter withdrew study drug supply, at which time 645 patients had been enrolled and 299 skeletal-related events had occurred. Based on the recommendation of the CALGB/Alliance Data and Safety Monitoring board, protocol treatment was terminated for all patients after July 2, 2012, with no further data being collected.
The zoledronic acid and placebo groups were generally balanced for age (median, 66 and 67 years), race (81% and 80% white), Gleason score (5–7 in 38% and 35%, 8–10 in 58% in both), prior therapy (eg, gonadotropin-releasing hormone [GnRH] agonist alone in 25% and 27%, GnRH agonist plus antiandrogen in 69% and 65%), metastatic sites (eg, bone in 97% and 96%, soft tissue in 10% and 8%), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 63% and 64%, 1 in 33% in both), prior skeletal-related event (13% and 12%), median alkaline phosphatase level (117 and 117.5 U/L), and median prostate-specific antigen level (6.9 and 6.8 ng/mL).
A total of 621 patients received at least one dose of study medication. Open-label zoledronic acid treatment was started in 49% of patients in the zoledronic acid group and 51% in the placebo group. Median time on study was 11.8 months in the zoledronic acid group and 13.6 months in the placebo group.
No Difference in Skeletal-Related Event Risk
Median time to first skeletal-related event was 31.9 months in the zoledronic acid group and 29.8 months in the placebo group (hazard ratio [HR] = 0.97, P = .39). In an exploratory analysis in the 82 patients with history of skeletal-related events prior to study entry, median time to first skeletal-related event was 31.9 months in zoledronic acid group and 17.6 months in the placebo group (HR = 0.56, 95% confidence interval = 0.31–1.02); prior skeletal-related event by treatment interaction was borderline significant (P = .054). There were no differences in time to first skeletal-related event between groups according to ECOG performance status or baseline alkaline phosphatase.
Median progression-free survival was 10.6 vs 9.2 months (P = .22), and median overall survival was 37.9 vs 36.0 months (adjusted HR = 0.88, P = .29).
Toxicity
Treatment was discontinued due to adverse events in 21% of patients in the zoledronic acid group vs 12% of the placebo group. Treatment-related grade ≥ 3 adverse events occurred in 14% vs 12%, with the most common including pain (3% vs 3%), hypophosphatemia (3% vs 2%), and hypocalcemia (3% vs 1%). Grade 3 osteonecrosis occurred in 3.2% vs 1.9%, with all cases considered treatment-related. Two patients in each group discontinued study treatment due to creatinine elevation.
The investigators concluded, “In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for [skeletal-related events].”
Matthew R. Smith, MD, PhD, of Massachusetts General Hospital Cancer Center-Yawkey, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported in part by grants from the National Cancer Institute, research awards from the Prostate Cancer Foundation, and by Novartis Oncology. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
