Zoledronic Acid Reduces Skeletal Complications, Bone Pain

CHICAGO—Zoledronic acid (Zometa) significantly decreased skeletal complications and bone pain in men with hormone-refractory prostate cancer and bone metastases, compared with placebo, according to an update of a phase III study presented at the 2003 Annual Meeting of the American Urological Association (abstracts 1472 and 1473).

After 24 months of follow-up, the percentage of men who had at least one skeletal-related event was 49% in the placebo group vs 38% in the treatment group, a relative reduction of 22% and an absolute reduction of 11%, reported Fred Saad, MD, associate professor of urology and director of urology oncology, Montreal Cancer Center, University of Montreal.

Among men treated with zoledronic acid, there was a 5-month delay in the median time to the first skeletal-related event and a 6.5-month delay in the time to the first pathologic fracture, compared with placebo.

"Probably the most important endpoint was the multiple event analysis that took into consideration the proportion of patients having skeletal-related events, the time between events, and the number of events that occurred per patient," Dr. Saad said. In the multiple events analysis, the risk of developing a skeletal complication was 36% lower for patients treated with the bisphosphonate (P = .002).

Differences in pain scores between zoledronic acid and placebo were statistically significant at 3, 9, 21, and 24 months. Men treated with zoledronic acid also had significantly less need for radiation treatments directed to bone, which suggests that the bisphosphonate provides improved pain control, Dr. Saad said.

"There were few adverse events that were unexpected, and renal toxicities were limited and identical to placebo at the 4-mg zoledronic acid dose. So we feel this is a new treatment option for patients with metastatic prostate cancer," he said.

When asked his opinion about the possible use of zoledronic acid earlier in the prostate cancer disease process, Dr. Saad said, "My gut feeling is that it will have a benefit, but we need a study to prove it. That is the next logical step, and a study is going to be started very shortly on that topic."

Study Protocol

The data presented in the two posters were from the full 24-month study of zoledronic acid in 643 men with advanced, hormone-refractory prostate cancer and at least one bony metastasis. Results in the same group of men after 15 months of follow-up, which were the first to show that a bisphosphonate was effective in treating or preventing skeletal complications in men with metastatic prostate cancer, were reported at last year’s annual meeting of the American Urological Association and published in the Journal of the National Cancer Institute (94:1458-1468, 2002).

The original 643 men were randomized to receive placebo or either 4 mg or 8 mg of zoledronic acid in a 15-minute infusion every 3 weeks. Of these, 208 completed the 15-month initial phase of investigation and 186 continued in the double-blind extension portion of the study.

Of the 214 men randomized to receive 4-mg zoledronic acid, 82 completed 15 months of treatment and 75 continued in the extension phase. After administration of the 8-mg dose of zoledronic acid was discontinued because of renal deterioration in some patients, these patients were reassigned to the 4-mg arm. Of these 221 men, 61 completed the initial phase and 53 entered the extension phase, but are not included in the current report. Among the 208 men randomized to the placebo group, 65 completed 15 months of treatment and 58 participated in the extension study.

Zoledronic acid significantly reduced the percentage of men who had a skeletal-related event, the primary endpoint of the study, at the P = .028 level. Skeletal-related events included any evidence of a pathologic fracture or spinal cord compression, radiation therapy or surgery to bone, or change in chemotherapy to treat bone pain.

Zoledronic acid delayed the onset of both skeletal complications and the appearance of the first pathologic fracture. The median time to the first skeletal-related event was 488 days in the zoledronic acid group vs 321 days in the placebo group (P = .009). The time to the first pathologic fracture was also significantly reduced with use of zoledronic acid.

Fewer Skeletal-Related Events

The bisphosphonate also decreased the annual incidence of skeletal complications. Among men treated with zoledron-ic acid, the mean number of skeletal-related events per year was 0.77 vs 1.47 among men on placebo (P = .005).

There was no significant difference in survival, a secondary endpoint of the investigation. The median survival was 546 days (18 months) among men who received zoledronic acid and 469 days (15.4 months) in men who took a placebo. Dr. Saad pointed out that the average survival rate for this patient population is close to 15 months.

Similar percentages of patients in the two arms of the study had elevated serum creatinine levels: 17.4% in the zoledronic acid group and 12.8% in the placebo group. The time to the first increase in serum creatinine also was similar. There was a small nonsignificant difference in the risk of a rise of serum creatinine associated with the use of zoledronic acid. The hazard ratio for elevated serum creatinine was 1.137 for men who received zoledronic acid.

Pain Relief

Although other bisphosphonates, such as alendronate (Fosamax), clodronate, and pamidronate (Aredia), have been suggested as a palliative measure when analgesics and radiation therapy fail to control pain from bone malignancies, they have not been shown to exert long-term effects in either single-arm open-label studies or randomized, placebo-controlled trials of men with prostate cancer, Dr. Saad said. The current study of zoledronic acid, he said, is the first to show that a bisphosphonate can exert consistent pain relief in men with prostate cancer that has metastasized to bone.

Although Brief Pain Inventory (BPI) scores rose over the entire study period, increases in pain scores were smaller in men treated with zoledronic acid, Dr. Saad said. Overall, BPI rose from baseline by more than 1.0 in men treated with a placebo and by about 0.6 for men treated with the bisphosphonate. The differences in pain score were significant at 3 months (P = .003), 9 months (P = .03), 21 months (P = .014), and 24 months
(P = .024).

Fewer men receiving zoledronic acid needed radiation therapy to control metastatic bone pain: 26% vs 33% of the patients in the placebo arm. The drug also delayed the need for radiotherapeutic treatment of bone pain. The median time to radiation therapy was not reached in the zoledronic acid group but was 655 days (21.5 months) in the placebo group (P = .056).

Analgesic scores did not differ among men on zoledronic acid or those on a placebo, which suggests that the bisphos-phonate may improve pain control without increasing the need for analgesics. The mean analgesic score was 1.04 in the zoledronic acid group and 1.17 in the placebo group.