How to Most Effectively Delay Skeletal Events in Patients with Bone Metastases from Solid Tumors?

Skeletal Events

Bone metastases from malignant tumors carry the risk of skeletal complications such as pathological fractures and the need for orthopedic surgery or radiotherapy to prevent spinal cord or nerve root compression. These skeletal-related events (SREs) represent a significant cause of morbidity, loss of mobility, and functional decline in oncology patients. Additionally, they are associated with pain, leading to a substantial decrease in quality of life, often requiring opioid therapy or radiotherapy. SREs are also linked to poorer prognosis and shorter survival of patients.

Denosumab

Denosumab is a monoclonal antibody against RANK ligand (RANKL) administered subcutaneously to prevent SREs in patients with solid tumors that have metastasized to the bone. Bone destruction induced by malignant tumors is primarily due to the activation of osteoclasts. RANKL is the main activator of osteoclasts and mediator of this resorption.

The prevention and delay of SREs were evaluated in three randomized double-blind studies with denosumab compared to zoledronic acid (ZA) in patients with prostate cancer, breast cancer, and other solid tumors or multiple myeloma. Denosumab demonstrated superior efficacy compared to ZA in patients with breast cancer, prostate cancer, and the overall population across all three studies. In the study involving patients with solid tumors (excluding breast and prostate cancer) or multiple myeloma, which included 1776 patients, denosumab demonstrated noninferiority to ZA with a 16% reduction in the risk of the first SRE during the study and a median time to the first SRE of 20.6 months compared to 16.3 months with ZA treatment.

Evaluated Population and Parameters

The cited ad hoc analysis included a subgroup of 1597 patients with solid tumors excluding prostate and breast cancer from the third study mentioned above. It excluded patients with multiple myeloma, who made up 10% of the population.

Patients were randomized in a 1:1 ratio to receive 120 mg denosumab s.c. and i.v. placebo or s.c. placebo and 4 mg ZA i.v. (dose adjusted based on creatinine clearance) every 4 weeks. Calcium supplementation of ≥500 mg and vitamin D ≥400 IU was recommended.

The primary endpoints were the time to the first SRE during the study and the time to the first and subsequent SREs. SREs were defined as pathological fractures (vertebral and non-vertebral), spinal cord compression, or the need for radiotherapy or surgery to the bone.

Pain was assessed using the 11-point Brief Pain Inventory-Short Form (BPI-SF) questionnaire. Monitored parameters included pain worsening, the impact of pain on seven aspects of daily life (overall activity, mood, walking ability, work, relationships with others, sleep, and enjoyment of life), and analgesic use.

Results

The most common solid tumors were non-small cell lung cancer (44%), renal cell carcinoma (10%), small cell lung cancer (7%), bladder cancer (4%), rectal cancer (4%), and colon cancer (4%).

Denosumab significantly prolonged the time to the first SRE during the study compared to ZA (21.4 vs. 15.4 months; hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.68–0.96; p=0.017) and reduced the risk of multiple SREs (328 vs. 374 events; relative risk [RR] 0.85; 95% CI 0.72–1.00; p=0.048). Comparable efficacy was observed across all individual types of solid tumors. The results indicated that treating 7.8 patients with denosumab instead of ZA for one year was needed to prevent one SRE.

Denosumab also significantly delayed the development of moderate to severe pain (HR 0.81; 95% CI 0.66–1.00; p=0.050), pain worsening (HR 0.83; 95% CI 0.71–0.97; p=0.016), and the impact of pain on daily activities in patients with baseline mild pain or less (HR 0.77; 95% CI 0.61–0.96; p=0.021).

The incidence of adverse events was 96% in both groups. Grade 3–4 hypocalcemia was more frequent in the denosumab group, mostly without clinical consequences (4% vs. 2%). Osteonecrosis of the jaw was reported in 0.8% of patients with denosumab and 1.1% of patients with ZA.

Conclusion

The analysis results indicated that denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and in preventing pain progression compared to zoledronic acid.

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Source: Henry D., Vadhan-Raj S., Hirsh V. et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer 2014; 22 (3): 679–687, doi: 10.1007/s00520-013-2022-1.