Zoledronic acid Tx cuts skeletal events in half

September 1, 2004

New Orleans--Data from a randomized clinical trial show that long-term treatment with the bisphosphonate agent zoledronic acid (Zometa) halved the rate of skeletal events in patients with advanced prostate cancer and bone metastases.

New Orleans-Data from a randomized clinical trial show that long-term treatment with the bisphosphonate agent zoledronic acid (Zometa) halved the rate of skeletal events in patients with advanced prostate cancer and bone metastases.

The magnitude of risk reduction during the 9-month extension phase exceeded the benefits observed during the 15-month randomized trial (J Natl Cancer Inst 2002; 94: 1458-68). The results support continued use of zoledronic acid until a beneficial effect is no longer apparent, a Canadian urologic oncologist said at the American Society of Clinical Oncology annual meeting.

"In the first 15 months, we reported a 36% reduction in the risk of skeletal events, but patients who lived beyond that continued to be at risk," said Fred Saad, MD, director of urologic oncology at the University of Montreal Hospital Center and Notre Dame Hospital, Montreal. "During those last few months, the risk was reduced by more than 50%. Among patients who live that long, the therapy is worth continuing because they are still at risk."

Of 422 patients randomized to zoledronic acid, 4 mg, or placebo, 147 completed the 15-month trial, and 133 agreed to enter the pre-planned 9-month extension, during which time they remained on assigned therapy.

9-month extension

"The idea behind the extension was to determine whether the benefits of therapy continued beyond 15 months," Dr. Saad told Urology Times. "Obviously, as treatment continues for a longer period of time, there is a risk of losing the benefit. Some clinical guidelines recommend continuing treatment indefinitely until there is no more benefit. We wanted to see whether there really is a benefit with continued treatment."

The primary endpoint of the 15-month study and the 9-month extension was the proportion of patients who had at least one skeletal-related event (SRE). Investigators defined SRE as pathologic fracture, spinal cord compression, radiation therapy to bone, surgery to bone, or a change in chemotherapy to treat bone pain.

During the 15-month trial, 33% of patients treated with zoledronic acid, 4 mg, had at least one SRE compared with 44% in the placebo group (p=.021). At the completion of the 9-month extension, SREs had occurred in 19% of zoledronic acid patients versus 38% of placebo patients (p=.017).

Multiple-event analysis of months 16 to 24 revealed a relative risk of 0.467 for treatment with zoledronic acid, representing a 53% risk reduction (p=.002). That compared with a 36% reduction in relative risk during the first 15 months (p=.004) and an overall 36% risk reduction for the entire follow-up period (p=.002).

Evaluation of SREs over time resulted in a skeletal morbidity rate of 0.42 SRE/year in the zoledronic acid group compared with 0.88 SRE/year in the placebo group during the extension phase (p=.016). During the first 15 months of follow-up, patients treated with zoledronic acid, 4 mg/day, had a skeletal morbidity rate of 0.80 SRE/year versus 1.49 SRE/year in the placebo group (p=.006).

Treatment with zoledronic acid also significantly prolonged the time to a first SRE during the randomized trial (p=.009) and during the extension (p=.036).

Another analysis of the study showed that patients who entered the study with a history of skeletal complications derived greater benefit from treatment with zoledronic acid compared with patients with no prior SREs. The analysis encompassed the entire 24 months of follow-up and showed that patients with a history of SRE had a 40% reduction in relative risk, compared with 33% for patients with no prior SRE.

Future studies will evaluate earlier initiation of zoledronic acid, including patients who have bone metastases but no SREs and those who have yet to develop bone metastases. Dr. Saad said there are animal data showing evidence that zoledronic acid can prevent metastases. Other studies will evaluate the bisphosphonate in combination with docetaxel-based chemotherapy.