Delaying skeletal-related events 
in men with metastatic PCa


Skeletal-related events (SREs) are one of the main sources of morbidity in men with metastatic castration-resistant prostate cancer (CRPC). SREs are defined as palliative radiation to bone, pathologic fractures, spinal cord compression, and surgery to bone.

The natural history of untreated bone metastases in men with metastatic CRPC has been elucidated from the placebo arm of a prospective, randomized trial comparing zoledronic acid with placebo.26 In the placebo arm, patients had a 49% chance of having at least one SRE within two years, and the median time to first SRE was 10.7 months. In this trial, zoledronic acid significantly prolonged the time to SREs and reduced the incidence of SREs compared with placebo and became the first agent FDA approved for the prevention of SREs in PCa patients.26


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In a more recent, large-scale, randomized, controlled trial comparing denosumab and zoledronic acid in men with metastatic CRPC, denosumab had improved efficacy in delaying time to first and subsequent SRE compared with zoledronic acid, with a median time to first SRE of 20.7 months compared to 17.1 months with zoledronic acid.27 Per NCCN guidelines, men with metastatic CRPC should be prescribed either zoledronic acid or denosumab. Osteonecrosis of the jaw is a rare AE of both agents (occurring in 1%-2% of patients).

Prior to initiating either therapy, a dental history should be taken and a brief oral exam performed. If the patient had recent dental procedures or has planned procedures, therapy should be delayed until complete healing has occurred, approximately three months (consult with patient’s dentist/orthodontist). Renal failure is a complication of zoledronic acid, so creatinine levels should be monitored before each dose, and dose adjustment or drug discontinuation is required if the creatinine rises.

Denosumab is not metabolized by the kidneys and creatinine levels do not need to be monitored during therapy, although denosumab has not been evaluated in PCa patients with a creatinine clearance of <30cc/min or on dialysis. In the clinical trial, severe hypocalcemia occurred in 5% of patients on denosumab and 1% on zoledronic acid. Therefore, calcium levels should be normalized at baseline and followed monthly for several months and then periodically.27 Likewise, calcium and vitamin D should be given to all patients on denosumab and zoledronic acid.


Two recently approved therapies that play a critically important role in treating advanced PCa (abiraterone and enzalutamide) have also been reported to delay time to SREs.28,29 Radium-223 is an alpha-emitting pharmaceutical targeting bone metastases with high energy, short range, alpha particles. Radium-223 improved overall survival in CRPC patients with bony metastasis by 3.6 months compared with placebo.30

In patients receiving six q4wk injections of radium-223, time to first SRE was delayed by 5.8 months compared with placebo.31 Radium-223 was approved by the FDA in May 2013 for CRPC and symptomatic bone metastases. Cabozantinib, an oral tyrosine kinase inhibitor with activity against hepatocyte growth factor receptor and vascular endothelial growth factor receptor 2, has also shown promising results in men with metastatic CRPC.32

In a phase 2 trial, 72% of patients had regression in soft tissue lesions and 68% had improvement on bone scans, including complete resolution of bone scan lesions in 12% of patients. Bone pain also improved in 67% of patients with a decrease in narcotic use in 56% of subjects.30 Phase 3 trials of cabozantinib are ongoing.


Conclusion


Urologists hold a unique clinical position in managing bone health as most of their patients are aging men, many of whom suffer from PCa and require ADT. When a urologist prescribes ADT, osteoclast activity is increased and bone loss is accelerated, thereby increasing fracture risk.

As a central caregiver for aging men, it is critically important that the urologist either evaluates and appropriately treats these patients to preserve bone health and lower fracture risk, or refers these patients to their primary care doctor for appropriate therapy.

Likewise, urologists are often the first practitioners to diagnose their PCa patients with bone metastases, and appropriate bone protective agents should be prescribed or the patients should be referred to a medical oncologist to obtain these therapies.

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