In 2011, a phase 3 study randomized 1,904 men with CRPC in a 1:1 ratio to receive 120 mg SQ denosumab plus IV placebo or 4 mg IV zoledronic acid plus SQ placebo every 4 weeks.1 The primary endpoint was time to first on-study skeletal-related event.
This trial found that the median time to first skeletal-related event was 20.7 months for patients treated with denosumab compared with 17.1 months for men treated with zoledronic acid (HR 0.82, 95% CI 0.71-0.95). Serious adverse events were comparable between denosumab (63%) zoledronic acid (60%).
Bone protective agents are recommended by many guidelines, including the EAU/EANM/ESTRO/ESUR/SIOG groups that recommend offering bone protective agents to patients with mCRPC and skeletal metastases to prevent osseous complications, and the NCCN guidelines that recommend bone protective agents in CRPC patients with bone metastases. But, Dr. Tombal mentions that these guidelines are offering protective agents for very late patients, prior to the era of abiraterone, enzalutamide, etc. Importantly, he points out that even in the era of these new androgen receptor agonists, skeletal-related events are still happening: in the PREVAIL trial, 32% of patients experienced an SRE at the time of analysis.2
In a recently published study assessing the incidence of skeletal-related events among patients with CRPC in the SEER-Medicare cohort.3 Among 2,234 men with CRPC, 896 (40%) had a skeletal-related event during follow-up, of which 74% occurred during the first year of follow-up. The overall incidence rate of events was 3.78 (95% CI 3.53-4.03) per 100 person-months. Interestingly, the incidence rate was 4.16 (95% CI 3.71-4.65) per 100 person-months prior to bone-targeted agents, which dropped to 3.60 (95% CI 3.32-3.91) per 100 person-months after bone-targeted agents.
Dr. Tombal notes that longer exposure to ADT, as a result of better treatment, increases the risk of non-pathologic fractures among these men. As has been discussed at length in this session, in the ERA 223 study,4 40% of patients were receiving bone protective agents at the time of study entry, and in a post-hoc analysis, bone protective agents significantly reduced the rate of fracture in both arms.
Dr. Tombal concluded his presentation highlighting why most mCRPC patients should receive bone protective agents:
- Bone is the most frequent site of metastasis in men with prostate cancer
- Development of bone metastasis is associated with disease progression, increased mortality, and risk of skeletal-related events
- Nonpathological fractures are increasingly seen in patients treated for long durations with androgen receptor inhibitors
- Bone protective agents significantly reduce the incidence of fractures and skeletal-related events
- The caveat is that we don’t know if the registered skeletal-related event dosage is required at an earlier stage of the disease
Presented by: Bertrand Tombal, MD, PhD, Professor and Chairman, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland
Read the Opposing Debate: Antiresorptive Therapy to Reduce SRE Risk in Men with Bone-mCRPC -- For Select Men with CRPC and Bone Metastases
- Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. 2011;377(9768):813-822.
- Loriot Y, Miller K, Sternberg CN, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (PREVAIL): Results from a randomised, phase 3 trial. Lancet Oncol 2015;16(5):509-521.
- Kawai AT, Martinez D, Saltus CW. Incidence of skeletal-related events in patients with castration-resistant cancer: An Observational Retrospective Cohort Study in the US. Prostate Cancer 2019 Jul 9;2019:5971615.
- Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019 Mar;20(3):408-419.
Further Related Content: Antiresorptive Therapy to Reduce SRE Risk for the Majority of Men with CRPC and Bone Metastases Presentation