SAN ANTONIO (EGMN) – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab group compared with those on zoledronic acid, Dr. Alison T. Stopeck reported at the San Antonio Breast Cancer Symposium.

“To put this in some perspective, the average life expectancy of these patients is 2½ to 3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time,” said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9). The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%). Hypocalcemia occurred in 6.1% of the denosumab group compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates – 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the U.S. Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It’s given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid. And unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

“This is a trial I think we’re all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we’d like to move earlier,” Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

圣安东尼奥(EGMN)——一项里程碑式直接比较研究的最新结果显示，与唑来膦酸相比，denosumab可使晚期乳腺癌和骨转移患者发生首起骨骼相关不良事件的中位时间多延后5个月，并使复合次要终点(包括首起骨骼相关事件或高血钙症)的中位发生时间多延后7.3个月。 

本项关键III期随机、双盲、双模拟研究纳入2,046例晚期乳腺癌和骨转移患者，其中1%为男性。患者随机分组，一组皮下注射120 mg denosumab，另一组静脉输注4 mg 唑来膦酸，两组的给药间隔均为每4周1次。 

此扩展分析的双盲治疗时间在跨度上比之前发表的(J. Clin. Oncol. 2010;28:5132-9)多了4个月。分析显示，denosumab组发生首起研究中骨骼相关事件(如骨折、骨髓压迫、或骨放疗或手术)的中位时间为32.4个月，而唑来膦酸组为27.4个月，差异显著(P = 0.0096)。denosumab组发生首起研究中骨骼相关事件或高钙血症的中位时间为32.4个月，而唑来膦酸组为25.1个月(P = 0.0076)。将分析时间延长至3年发现，denosumab组发生≥1起骨骼相关事件的患者比例为32.9%，而唑来膦酸组为38.9%，相对危险度降低了15.4%。在这额外4个月的双盲治疗期间，多发生了100起骨骼相关事件，使denosumab组和唑来膦酸组此类事件的总数分别达到526 起和669起；危险度降低22%(P = 0.0008)。并且随着时间推移，两组的事件曲线继续呈分开趋势。两组的总生存率和疾病进展率相似。 

在不良事件方面，肾毒性明显更常见于唑来膦酸组(9.4% 对5.4%)，骨痛和(或)流感样症状等急性期反应也明显更常见于唑来膦酸组(28.2%对10.7%)。denosumab组低钙血症发生率为6.1%，而唑来膦酸组为3.7%。两组的颚骨坏死发生率相似(≤2.5%)。 

本研究由安进公司和第一三共株式会社共同申办。研究者声明是denosumab销售商安进公司和唑来膦酸销售商诺华公司的顾问，并从这两家公司获得研究资金。 

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