Bone Targeted Therapy and Skeletal Related Events in the Era of Enzalutamide and Abiraterone Acetate for Castration Resistant Prostate Cancer with Bone Metastases - Beyond the Abstract

Bone targeted therapy with zoledronic acid or denosumab has been shown to reduce the rates of skeletal-related events when initiated at the time of castrate resistance for prostate cancer. However, when studied in the hormone-sensitive setting there was no benefit to early initiation of zoledronic acid. In the current era of effective, life-prolonging therapies in castrate-resistant prostate cancer (CRPC) the benefit of early initiation of bone-targeted therapies with associated toxicities is unclear.

To investigate the impact of bone targeted therapies in the modern era, we performed a retrospective analysis of 249 patients treated at a single institution with a median follow-up of nearly eight years where the timing of bone targeted therapy was investigated. Those who initiated bone targeted therapy with either zoledronic acid or denosumab up to one month before second-line therapy for castrate-resistant prostate cancer were compared to those who never initiated or delayed therapy. On multivariable analysis, patients with four or more bone metastases at diagnosis of metastatic CRPC who received bone targeted therapy with abiraterone acetate or enzalutamide as first-line therapy had a 42% reduced risk of developing a skeletal-related event (hazard ratio [HR] 0.58; 95% confidence interval [CI]: 0.36-0.95) compared to those who never received bone targeted therapy or received it in the second line. No such effect was observed in patients with one to three bone metastases.

Our study suggests that a more nuanced approach to the initiation of bone-targeted therapies in CRPC may be appropriate despite the limitations. It is a retrospective analysis from a single institution; given the minimal number of patients who pursued bone-targeted therapy with subsequent lines of therapy for CRPC, a dedicated analysis comparing early with later initiation could not be performed. Furthermore, our analysis was limited to skeletal-related events which may be a late event, and to truly judge the benefit of therapy all patients should be followed until death. With nearly eight years of follow-up with only 20% alive at the time of the analysis, we feel we captured the most informative data.

Bone targeted therapy remains an important aspect of care for castrate resistant prostate cancer and should unequivocally be used in conjunction with radium-223 or in the setting of a prior skeletal-related event. Our data suggest that in patients with four or more bone metastases, early initiation of therapy remains critical to reducing skeletal-related events. However, among those with one to three bone metastases pursuing enzalutamide or abiraterone for first-line therapy of CRPC, it may be safe to defer initiation of bone targeted therapy, especially if responding but ultimately more work is needed to define optimal timing for commencing bone targeted therapy in these patients.

Written by: Brad McGreggor, MD, Instructor, Medicine, Harvard Medical School, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, GU Network Liason, CSO Cabinet, Dana-Farber Cancer Institute, Boston, Massachusetts 

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