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Bone biomarkers and overall survival (OS) in men with castrate resistant prostate cancer (CRPC) and skeletal metastases: Updated results from SWOG 0421, a phase III trial of docetaxel +/- atrasentan

Date

09 Oct 2016

Session

Poster display

Presenters

Primo Lara

Citation

Annals of Oncology (2016) 27 (6): 243-265. 10.1093/annonc/mdw372

Authors

P.N. Lara1, M. Plets2, C. Tangen2, E. Gertz3, N.J. Vogelzang4, D.I. Quinn5, I. Thompson6, M. van Loan3

Author affiliations

  • 1 Internal Medicine/hematology-oncology, University of California Davis Cancer Center, 95817 - Sacramento/US
  • 2 Statistics, Fred Hutchinson Cancer Research Center, Seattle/US
  • 3 Usda, Univesity of California Davis, Davis/US
  • 4 Medical Oncology, US Oncology Research c/o Comprehensive Cancer Crts of NV, Las Vegas/US
  • 5 Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles/US
  • 6 Urology, University of Texas Health Science Center San Antonio, San Antonio/US
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Resources

Background

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.

Methods

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.

Results

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 

Conclusions

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

Funding

National Cancer Institute (USA)

Disclosure

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.

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