The current landscape for FDA approved uses of osteoclast-targeted therapy is as follows:
- Oral bisphosphonates (ie. alendronate, risedronate, ibandronate): men at risk for fragility fractures.
- Zoledronic acid 5 mg q12 months (Reclast): men at risk for fragility fractures.
- Zoledronic acid 4 mg q3-4 weeks (Zometa): men at risk for skeletal-related events.
- Denosumab 60 mg q6 months (Prolia): men at risk for fragility fractures
- Denosumab 120 mg q4 weeks (Xgeva): men at risk for skeletal-related events.
In the CALGB 70604 study, Himelstein and colleagues assessed the effect of longer-interval vs standard dosing of zoledronic acid on skeletal-related events among patients with breast, prostate, multiple myeloma bone metastasis.2 For this trial, patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Among these 1,822 patients, 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least one skeletal-related event within 2 years of randomization (risk difference of -0.3%; p < .001 for noninferiority). Although there was no difference in SRE incidence, zoledronic acid every 4 weeks had lower C-telopeptide levels than the 12-week dose, suggesting differences in osteoclast inhibition.
Dr. Smith notes that there are several limitations associated with the CALGB 70604 trial:
- There can be no assumption of constancy, a requirement for valid inference for non-inferiority trials.
- This study included some patients (men with HSPC) with no potential for benefit.
- SRE definition was different from previous studies.
- The primary analysis was 24-month event rate, but only 43% completed the study at 2 years (median follow-up only 14 months).
- The non-inferiority margin included a clinically important difference.
- The longer dosing interval did not improve safety and tolerability.
Dr. Smith’s conclusions for skeletal-related events are that (i) SREs are a distinct set of clinical problems related to cancer progression to the bone; (ii) approved therapies for osteoporosis are not sufficient to prevent SREs; (iii) zoledronic acid (4 mg q3-4 weeks) and denosumab (120 mg q4 weeks) significantly decrease SREs in mCRPC and bone metastases; (iv) zoledronic acid (4 mg q12 weeks) might be sufficient for SRE prevention, but evidence for efficacy is weak and has no proven safety benefit; (v) the optimal treatment duration for SRE prevention is undefined.
Presented by: Matthew R. Smith, MD, Ph.D., Professor, Harvard Medical School, Medicine, Assistant in Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_m at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland
- Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004 May 24;164(10):1108-1112.
- Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial. JAMA 2017 Jan 3;317(1):48-58.
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