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APCCC 2019: The Best Use of Osteoclast-Targeted Therapy in CRPC

Basel, Switzerland (UroToday.com) Dr. Matthew R. Smith provided a summary detailing the best use of osteoclast-targeted therapy for patients with bone metastatic castration-resistant prostate cancer (mCRPC). Dr. Smith noted that it is important to distinguish between skeletal-related events and fragility fractures secondary to osteoporosis. Fragility fractures are possible in all men, at the site of normal bone, and have an increased incidence among patients receiving prostate cancer treatment. Skeletal related events are only among men with bone metastasis, are at the site of the bone metastasis, and decrease in incidence with the utilization of prostate cancer treatment.

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.
The National Osteoporosis Foundation Fracture Prevention Guidelines suggests that consideration for FDA-approved medical therapies should be based on the following: (i) a vertebral or hip fracture, (ii) a femoral neck or spine T-score <= -2.5, (iii) a FRAX 10-year probability of a hip fracture >= 3% or 10-year probability of any major fracture >= 20%. Interestingly, most fractures occur in patients without osteoporosis. In a study of 149,524 post-menopausal women with a mean age of 65 years, 82% of 2,259 women with fragility fractures had a baseline T-score of > -2.5.1

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 fragility fractures and osteoporosis are that (i) fragility fractures are common in men, and age, prior fracture, and low bone mineral density are the strongest predictors; (ii) in men with prostate cancer, fracture risk is increased by ADT and androgen pathway inhibitors; (iii) assessment of fracture risk should include evaluation of both clinical risk factors and bone mineral density; (iv) treatment-related fractures are preventable.

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

References:
  1. 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.
  2. 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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