Skeletal metastasis is seen in most CRPC patients and is a common source of morbidity. We previously reported that bone biomarkers in CRPC patients are independently prognostic for OS, and that in men with highly elevated markers there is benefit from bone-targeted therapy (Lara, et al. JNCI 2014). Here we report our prospectively planned classification & regression tree (CART) analysis of clinical covariates and bone biomarkers as part of the phase III S0421 trial of docetaxel +/- atrasentan.
Markers for bone resorption [N-telopeptide (NTx) & pyridinoline (PYD)] & formation [C-terminal collagen propeptide (CICP) & bone alkaline phosphatase (BAP)] were measured in pre-treatment sera from men on S0421. Bone biomarkers & baseline clinical covariates were included in a Cox model for OS; significant variables were allowed to compete in a CART analysis to identify prognostic groups using CTREE in the R package "party". Hazard ratios (HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox PH model. Kaplan Meier curves for each prognostic group defined by the tree were constructed.
750 men with evaluable bone marker & clinical data were included. Each bone marker significantly contributed to the final Cox model, with higher levels associated with worse OS. Cox stepwise selection identified BAP, CICP, PYD, hemoglobin (Hgb), pain score, age, black race, PSA, and visceral disease as associated with OS. CART analysis selected CICP, BAP, Hgb, & pain score for the final model, & identified 5 prognostic groups:
|Prognostic Group||Description||N||Median OS (months)||Hazard Ratio (95% CI)||p-value|
|1||Hgb 11.3 CICP 6.8 Worst pain > =4||144||15.3||0.79 (0.63, 0.99)||0.04|
|4||Hgb > 11.3 CICP > 6.8 Worst pain |
Elevated serum levels of bone biomarkers are strongly associated with worse OS in CRPC. CART analysis incorporating bone biomarkers identified five distinct prognostic CRPC groups with differential OS outcomes. These results further define & establish the role of bone biomarkers in the design and conduct of CRPC clinical trials.
Clinical trial identification
ClinicalTrials.gov NCT00134056; NCI 5R01-CA120469, CA180888 and CA180819
Legal entity responsible for the study
Southwest Oncology Group (SWOG) and the University of California Davis
National Cancer Institute (USA)
P.N. Lara: In the past 3 years I have served as a consultant (advisory board or DSMC member) for Clovis, Exelixis, Pfizer, Teva, Halozyme, Novartis, Sanofi, LPath, Lilly, Astra Zeneca, Bayer, and Genentech/Roche.
D.I. Quinn: Sanofi, Astellas, and Bayer for honoraria (ad boards) and Dendreon and Sanofi for trial support.
All other authors have declared no conflicts of interest.