Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events
Open accessAbstract
In this analysis of a phase III trial in patients with castration-resistant prostate cancer and bone metastases, treatment with denosumab reduced the risk of skeletal complications vs zoledronic acid regardless of whether the end point was defined as SSE or SRE. Both SSEs and SREs were associated with development of moderate/severe pain among patients with no/mild pain at baseline. Background In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. Patients and methods Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. Results Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar ( n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development ( P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. Conclusion In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.
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- Authors
- Smith, M. R., Coleman, R. E., Klotz, L., Pittman, K., Milecki, P., Ng, S., Chi, K. N., Balakumaran, A., Wei, R., Wang, H., Braun, A., & Fizazi, K.
- Affiliations
- Massachusetts General Hospital (US)
- Sunnybrook Health Science Centre (CA)
- Queen Elizabeth Hospital (AU)
- Poznan University of Medical Sciences (PL)
- St John of God Subiaco Hospital (AU)
- BC Cancer Agency (CA)
- Amgen (United States) (US)
- Université Paris-Sud (FR)
- Corresponding author
- Smith, M.R.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 26
- Issue
- 2
- Pages
- 368-374
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC4304378
- OpenAlex
- W2153871840
- Cited by
- 145
- References
- 22
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 11 · 2023: 5 · 2022: 17 · 2021: 12 · 2020: 7 · 2019: 10 · 2018: 19 · 2017: 21 · 2016: 18 · 2015: 17 · 2014: 2
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Amgen
- National Institutes of Health (5k24ca121990-07)
- National Cancer Institute (K24-CA121990)
- Topics
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- denosumab, zoledronic acid, castration-resistant prostate cancer, bone metastasis, skeletal-related events, pathological fracture, spinal cord compression, bisphosphonates, bone pain, RANKL inhibition, treatment efficacy comparison, Brief Pain Inventory-Short Form, radiopharmaceuticals
- MeSH terms
- Denosumab, Aged, Bone Neoplasms, Double-Blind Method, Humans, Male, Middle Aged, Bone Density Conservation Agents, Prostatic Neoplasms, Castration-Resistant
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