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A phase 3 randomized trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer
Lawrence Karsh, MD1, Matthew Smith, MD, PhD2, Neal Shore, MD, FACS3, Karim Fizazi, MD, PhD4, Michael Carducci, MD5, Ronaldo Damião, MD, PhD6, Janet Brown, MD7, Piotr Milecki, MD, PhD8, Huei Wang, PhD9, Roger Dansey, MD9, Carsten Goessl, MD9.
1The Urology Center of Colorado, Denver, CO, USA, 2Massachusetts General Hospital Cancer Center, Boston, MA, USA, 3Carolina Urological Research Center, Myrtle Beach, SC, USA, 4Institut Gustave Roussy, University of Paris, Villejuif, France, 5Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 6Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil, 7Cancer Research UK Clinical Centre, Leeds, United Kingdom, 8Wielkopolskie Centrum Onkologii, Poznan, Poland, 9Amgen Inc., Thousand Oaks, CA, USA.

BACKGROUND: In patients with advanced hormone-refractory (castration-resistant) prostate cancer (CRPC), bone metastases are a common finding. Tumor-associated bone destruction is mediated through RANKL activation of osteoclasts leading to skeletal-related events (SRE), which cause significant morbidity and health-economic burdens. Inhibition of RANKL, a central mediator of osteoclast activation and differentiation, may delay or prevent SREs. Denosumab is an investigational fully human monoclonal antibody against RANKL. This phase 3, randomized, double-blind, active-controlled trial compared the efficacy and safety of denosumab vs. zoledronic acid (ZA) in men with metastatic CRPC.
METHODS: Patients (n = 1901) with CRPC and at least 1 site of bone metastasis, but without prior IV bisphosphonate use, received either subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo (n = 950), or SC placebo and IV ZA 4 mg (n = 951) every 4 weeks. The dose of ZA was adjusted for creatinine clearance per the Zometa® label. All patients were instructed to take supplemental calcium and vitamin D. The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression.
RESULTS: Denosumab significantly delayed the time to first on-study SRE compared with ZA, (HR 0.82; 95% CI: 0.71, 0.95; P = 0.008.) The median time to first on-study SRE was 20.7 months in the denosumab group compared with 17.1 months in the ZA group, a difference of 3.6 months. Denosumab also significantly delayed the time to first and subsequent on-study SRE (multiple event analysis) (HR 0.82; 95% CI: 0.71, 0.94; P = 0.004). Patients receiving denosumab had greater suppression of the bone turnover markers urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BSAP) compared with ZA (P < 0.0001 for both markers). Overall, adverse event (AE) rates (97% in each group) and serious AEs (63% denosumab, 60% ZA) were similar, without an apparent relationship to investigational product administration. AEs of hypocalcemia were reported in 13% and 6% of denosumab and ZA patients. Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab compared with 12 (1.3%) ZA patients (P = 0.09). Overall survival (HR 1.03; 95% CI: 0.91, 1.17; P = 0.65) and time to cancer progression (HR 1.06; 95% CI: 0.95, 1.18; P = 0.30) were similar between treatment arms.
CONCLUSIONS: Denosumab 120 mg, administered subcutaneously every 4 weeks, demonstrated superiority over ZA administered by intravenous infusion every 4 weeks in delaying or preventing SREs in men with bone metastases from CRPC. Adverse events were consistent in both treatment groups with those previously reported in men with advanced prostate cancer.


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