Investigators for Study 136 say that an additional 4 months of follow-up data have confirmed earlier findings that denosumab (Xgeva) is superior to zoledronic acid (Zometa) at preventing skeletal-related events (SRE) in patients with breast cancer that has metastasized to their bones. "This extended data analysis showed that denosumab was superior to zoledronic acid, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than with zoledronic acid," said Alison Stopeck, MD, lead author and an associate professor of medicine at Arizona Cancer Center in Tucson.
Stopeck added that significantly fewer patients in the denosumab arm suffered pathologic fractures or required radiation to the bone compared with the group taking zoledronic acid. "These results reinforce the superior efficacy profile of denosumab versus zoledronic acid and provide additional reassurance of the safety profile of this drug. I feel confident that denosumab can prevent debilitating and costly bone complications [in these patients]," Stopeck said.
The international, randomized, doubleblind, phase III trial randomized 2046 adults with advanced breast cancer and confirmed bone metastases to 120 mg of denosumab, administered subcutaneously, plus intravenous placebo every 4 weeks (n = 1026); or to 4 mg of zoledronic acid administered intravenously and placebo administered subcutaneously every 4 weeks (n = 1020). All patients were given supplemental calcium and vitamin D. The patients had not received bisphosphonate treatment prior to study onset. Unlike most breast cancer trials, which include only women, ~1% of patients in this study were men, which Stopeck said reflects the real-world incidence of breast cancer in men.
Compared with zoledronic acid, Stopeck reported that use of denosumab extended the median time to first on-study SRE by 5 months (27.4 mo vs 32.4 mo, respectively; P
= .0096). In the subgroup of patients who experienced ?1 SRE, denosumab was associated with a 4.5% relative risk reduction at 12 months, an 11.4% relative risk reduction at 18 months, and a 15.4% relative risk reduction compared with zoledronic acid. Overall survival and disease-free progression were similar in both groups.
In a multiple events analysis, denosumab reduced the risk of first and subsequent SREs by 22%, a difference that Stopeck said was highly statistically significant (P
= .0008). Patients taking denosumab experienced 526 SREs overall, compared with 669 for patients treated with zoledronic acid. Stopeck emphasized that "the curves between the two treatment arms [for SREs] continued to separate over the 4-month extended analysis."
No new safety signals emerged over the 4-month extension study. Nearly all patients in the trial experienced at least 1 adverse event, and similar proportions in each arm experienced a serious adverse event (Table
). The zoledronic acid arm had nearly double the rate of adverse events related to renal toxicity compared with the denosumab group. The zoledronic acid group also had a higher rate of hypocalcemia compared with the denosumab group, whereas osteonecrosis of the jaw was more common in the denosumab arm than the zoledronic acid arm (P
= .29). The rate of acute phase reactions, such as bone pain and flu-like symptoms, was much higher in the zoledronic acid arm than in the denosumab arm. Stopeck pointed out that while 15% of patients taking zoledronic acid missed a dose or had a dose reduction to manage an adverse event, no patient taking denosumab missed any doses during the trial because of toxicity.
A subanalysis of Study 136 showed that patients taking denosumab experienced less pain than those taking zoledronic acid, based on data from a patient-completed Brief Pain Inventory. Patients randomized to denosumab said it took 70 days for the drug to reduce pain levels to where they no longer interfered with daily activities compared with 86 days for zoledronic acid (P
= .09). Pain took a median of 394 days to worsen for the patients given denosumab versus 310 days for those receiving zoledronic acid (P
Investigators are also looking to see whether denosumab can prevent bone metastases in patients with cancer. "We want to manipulate the bone microenvironment to prevent metastases," Stopeck said. D-CARE, a placebo-controlled trial that is looking at adjuvant therapy in breast cancer, has started to enroll high-risk patients with early-stage disease and will evaluate denosumab's effect on disease-free survival and bone metastasis-free survival. "I feel confident that Xgeva can provide patients with advanced breast cancer that have developed a bone metastases an excellent option to prevent debilitating and costly bone complications," Stopeck concluded.
The FDA approved denosumab on November 18, 2010, to prevent SREs in patients with bone metastases from solid tumors. It has not been approved for patients with multiple myeloma. Stopeck disclosed that her potential conflicts of interest include Amgen and Novartis, makers of these two drugs.