Efficacy of Zoledronic Acid or Denosumab with Stereotactic Radiotherapy in Inoperable Vertebral Bone Metastases: A Randomized Controlled Study

The primary objective of this study is to evaluate the efficacy of adding **zoledronic acid** or **denosumab** to stereotactic radiotherapy in the treatment of vertebral metastases. This evaluation is based on a cost-utility analysis within a randomized phase 3 study. The clinical relevance of this objective lies in determining whether the addition of these agents can enhance treatment outcomes for patients with inoperable vertebral bone metastases, potentially improving quality of life and treatment efficiency.

Secondary objectives include:

• Cost-effectiveness analysis
• Budget impact analysis
• Determination of vertebral compression fracture-free survival
• Bone complication-free survival
• Assessment of toxicity
• Assessment of pain control
• Assessment of local control of irradiated tumor lesions
• Assessment of neoplastic spinal instability
• Assessment of bone density
• Biological collection to determine immunological response profiles and markers of bone remodeling, and the impact of zoledronic acid or denosumab on these biomarkers
• Determination of a predictive model for bone fracture occurrence at 1 year using deep learning based on imaging examinations

The clinical trial involves **patients** who are men or women aged 18 years and older, diagnosed with inoperable vertebral bone metastases, and are candidates for treatment with stereotactic radiotherapy. The sponsor has not provided the total number of participants. The study population was selected based on specific criteria, including a diagnosis of cancer with inoperable thoracic and/or lumbar vertebral metastases, a life expectancy greater than one year, and a World Health Organization (WHO) performance status of 2 or less. Participants must also be affiliated with or benefit from the social security system. Both male and female subjects are included, and the trial does not involve a vulnerable population. Lifestyle considerations such as effective contraception are required for women of childbearing age. The trial aims to evaluate the efficacy of adding zoledronic acid or denosumab to stereotactic radiotherapy in the treatment of vertebral metastases, based on a cost-utility analysis and a randomized phase 3 study.

The clinical trial is a **randomized**, controlled, open-label, multicenter study designed to evaluate the efficacy of adding **zoledronic acid** or **denosumab** to stereotactic radiotherapy in the treatment of inoperable vertebral bone metastases. The trial aims to assess the cost-utility and cost-effectiveness of these treatments through a phase III study. The trial is expected to run from June 23, 2020, to June 23, 2027, with a maximum treatment period of 12 months for each participant. Participants will be randomly assigned to receive either **denosumab** via subcutaneous injection or **zoledronic acid** via intravenous infusion, in addition to their standard stereotactic radiotherapy.

Study visits are structured to include an initial screening visit, where eligibility criteria such as age (≥18 years), life expectancy (greater than 1 year), and performance status (WHO or PS ≤ 2) are confirmed. Participants must provide informed consent and meet all inclusion criteria, including effective contraception for women of childbearing age. Follow-up visits are scheduled at 6, 12, and 24 months post-initiation of radiotherapy to assess primary and secondary endpoints, including overall survival, cost-effectiveness, and quality of life measures. The end-of-study visit will occur at the conclusion of the 24-month follow-up period.

Participant involvement is expected to last up to 24 months, with conditions for early termination including withdrawal of consent, adverse events, or any situation where continued participation is deemed not in the participant's best interest by the investigator. The primary endpoint focuses on life gained in good health, with secondary endpoints including survival without vertebral compression fractures, bone complications, and assessments of pain control and bone density. The trial will also evaluate acute and delayed toxicity, local control of irradiated tumor lesions, and the sensitivity and specificity of fracture risk detection algorithms.

The clinical trial involves the administration of **denosumab**, marketed under the name XGEVA, which is provided as a 120 mg **solution for injection** in a pre-filled syringe. This experimental medication is administered via **subcutaneous injection**. The dosing schedule for denosumab is set at a maximum daily dose of 120 mg, with a total treatment period not exceeding 12 months. The active substance, denosumab, is a protein-based therapeutic agent, specifically categorized as "Protein - Other." The pharmaceutical form is a solution for injection, and the product is manufactured by Amgen Europe B.V. Compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol.

In addition to denosumab, the study also includes the administration of **zoledronic acid monohydrate**, marketed as Zometa, which is provided as a 4 mg/100 ml **solution for infusion**. This comparator treatment is administered via **intravenous use**. The maximum daily dose for zoledronic acid is 4 mg, with a cumulative dose not exceeding 52 mg over a 12-month period. Zoledronic acid monohydrate is a chemically synthesized active substance, and the product is manufactured by Phoenix Labs Unlimited Company. The administration of zoledronic acid will be conducted in accordance with the study protocol, and participant compliance will be closely monitored to ensure accurate data collection and analysis.

The efficacy of the clinical trial will be assessed through a comprehensive evaluation of both primary and secondary endpoints. The primary endpoint focuses on the quality of life gained in good health, which will be measured by calculating the Incremental Cost-Effectiveness Ratio (ICER). This involves identifying care consumption, measuring costs, estimating overall survival, and calculating utilities using the EQ5D-5L questionnaire. The Relative Overall Cost Ratio (ROCR) will be measured at 6 months and 24 months after the start of radiotherapy.

Secondary endpoints include a cost-effectiveness analysis through the calculation of a Differential Cost Outcome Ratio (DCOER), expressed as a cost per life-year gained, and measured at 6 months and 24 months from the start of radiotherapy. Additional analyses will include a budget impact analysis, survival without **vertebral compression fractures** (CVF) estimated at 6, 12, and 24 months, and survival without bone complications at the same intervals. Acute and delayed toxicity will be assessed according to CTCAE 5, while pain control will be evaluated using the Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI) at inclusion, 6, 12, and 24 months.

Local control of irradiated tumor lesions will be monitored through MRI and TAP and/or PET scans, with assessments at 6 and 12 months. The Neoplastic Spinal Instability Score (NSSI) will be evaluated at inclusion, 6, and 12 months. Bone density will be assessed via bone densitometry at inclusion, 6, and 12 months. Additionally, markers of immune response and bone remodeling will be measured, and the sensitivity and specificity of an algorithm for detecting the risk of fracture at 1 year will be evaluated.