Platinum Priority – Prostate CancerEditorial by Peter I. Croucher, Belinda S. Parker, Niall Corcoran and Michael J. Rogers on pp. 51–52 of this issueBone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer
Introduction
Worldwide, prostate cancer is the fifth most common cause of cancer death in men, with an estimated 307 000 deaths in 2012 [1]. Docetaxel plus prednisone has been the standard first-line therapy for symptomatic metastatic castration-resistant prostate cancer (CRPC) [2] since 2004, with a median overall survival of approximately 18 mo [3]. More recently, improved survival has been achieved with hormonal agents (abiraterone, enzalutamide), among other treatments [4], [5], [6], [7], [8].
Understanding prognostic factors for survival in metastatic CRPC is important for trial design as well as for informing patients about therapeutic options. Previous studies have identified prognostic variables based on disease characteristics such as prostate-specific antigen (PSA) level [9], PSA doubling time [10], PSA nadir [11], Gleason score [9], presence of visceral metastases [9], performance status [9], [12], and pain or analgesic use [12], [13]. Hemoglobin [9], [12], [14] and lactate dehydrogenase (LDH) [9], [12] have also been identified as independent prognostic factors. Of particular interest are bone-specific parameters, including history of previous skeletal-related event (SRE) [15], [16], pathologic fracture [17], urinary N-telopeptide (uNTx) [14], [18], [19], [20], alkaline phosphatase [9], and bone-specific alkaline phosphatase (BSAP) levels [14], [18], [19], which have demonstrated prognostic value. Notably, many of these factors were identified in datasets obtained prior to docetaxel approval, and the analyses were based on small sample sizes.
In this analysis, we examine the impact of baseline variables in a phase 3 trial [21] of bone-targeted agents (denosumab vs zoledronic acid). The objective of this study was to evaluate the risk reduction for time to first SRE between these agents; therefore, the study was not prospectively designed to collect all potential covariates for survival. The objective of this ad hoc analysis was to confirm and extend previously reported prognostic models in a large contemporary dataset.
Section snippets
Study design and patients
The trial was a randomized, double-blind, phase 3 study comparing denosumab and zoledronic acid in 1901 men (clinicaltrials.gov identifier NCT00321620) [21]. Patients had CRPC (defined as rising PSA levels despite circulating testosterone levels of <0.50 ng/ml), radiological evidence of bone metastasis, but no known brain metastases, and an ECOG score ≤ 2. Baseline demographic and disease characteristics were similar between treatment groups and no differences in overall survival were observed
Patients
Baseline demographics and disease characteristics for the overall study population are shown in Table 1. Median (95% confidence interval [CI]) overall survival time was 20 (18, 21) mo.
Univariate analyses
Point estimates for each variable are shown in Table 2. The bone-specific markers alkaline phosphatase, BSAP, and uNTx were each found to be predictors of survival (all p < 0.0001; Fig. 1). Two other bone parameters, pain and history of SRE, were also significant in the univariate analysis (both p < 0.0001). PSA <10
Discussion
In this analysis from the largest prospective clinical trial of CRPC patients with bone metastases (n = 1901), we demonstrate that bone-related parameters are good prognostic variables for overall survival. The analyses reported here both confirm previously identified variables and identify two new prognostic factors. As a whole, this analysis emphasizes the compelling prognostic value of bone-related factors in patients with bone metastases from CRPC. It is well recognized that the population of
Conclusions
In conclusion, bone-related parameters were found to be strong predictors of overall survival in addition to established disease stage factors in multivariate analyses using a large contemporary trial population of metastatic CRPC patients. The main utility of these findings is in the stratification of prospective clinical trials, although survival prediction in routine clinical practice is also feasible.
Presented at the annual meeting of the American Society of Clinical Oncology 2012.
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