Abstract
A clinical-genetic (CG) circulating tumor DNA (ctDNA)-based prognostic model for predicting overall survival (OS) in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with potent androgen receptor inhibition (Alliance).
Author
Susan Halabi
Department of Biostatistics and Bioinformatics, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University School of Medicine, Durham, NC
info_outline
Susan Halabi, Bin Luo, Siyuan S Guo, Todd Knutson, Jacqueline Lyman, Anna Kobilka, Himisha Beltran, Emmanuel S. Antonarakis, Jonathan E. Rosenberg, Matt D. Galsky, Charles J. Ryan, William Kevin Kelly, Eric J. Small, Michael J. Morris, Scott M. Dehm, Andrew J. Armstrong
Full text
Authors
Susan Halabi
Department of Biostatistics and Bioinformatics, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University School of Medicine, Durham, NC
info_outline
Susan Halabi, Bin Luo, Siyuan S Guo, Todd Knutson, Jacqueline Lyman, Anna Kobilka, Himisha Beltran, Emmanuel S. Antonarakis, Jonathan E. Rosenberg, Matt D. Galsky, Charles J. Ryan, William Kevin Kelly, Eric J. Small, Michael J. Morris, Scott M. Dehm, Andrew J. Armstrong
Organizations
Department of Biostatistics and Bioinformatics, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University School of Medicine, Durham, NC, Duke University, Durham, NC, Duke University Department of Biostatistics and Bioinformatics, Durham, NC, University of Minnesota, Minneapolis, MN, Dana-Farber Cancer Institute, Boston, MA, University of Minnesota Masonic Cancer Center, Minneapolis, MN, Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, Mount Sinai School of Medicine, New York, NY, Prostate Cancer Foundation, Santa Monica, CA, Department of Medical Oncology and Urology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, Memorial Sloan Kettering Cancer Center, New York, NY, Cancer Institute Center for Prostate and Urologic Cancer, Duke University Medical Center, Durham, NC
Abstract Disclosures
Research Funding
National Cancer Institute
Background:
We have previously developed and validated a clinical prognostic model of OS in mCRPC men that included these variables: performance status, disease site, opioid analgesic use, lactate dehydrogenase, albumin, hemoglobin, prostate specific antigen, and alkaline phosphatase. The goal of this analysis is to improve upon the clinical model of OS by incorporating ctDNA pathogenic genetic alterations (PGAs).
Methods:
Data from the A031201 phase 3 trial of enzalutamide+/- abiraterone were used to develop and validate the CG model of OS. Cell-free DNA was isolated from plasma and analyzed using a 69-gene targeted DNA-sequencing assay for detection of ctDNA PGAs. Genetic features were identified based on feature importance using a random survival forest and the final CG model was trained including clinical and selected genetic factors. Model discrimination was assessed using time-dependent area under the receiver operating characteristic curve (tAUC).
Results:
Data were available on 776 patients. In addition to clinical variables, the model included in this order: gains in AR and the AR enhancer, MYC, RSPO2, and losses and/or PGAs of ZBTB16, PTEN, MSH6, PPP2R2A, NKX3-1, TP53, FANCA, RB1, APC, CHD1, and BRCA2, and ichorCNA tumor fraction. tAUCs in clinical and CG models were 0.72 (95% CI=0.72-0.73) and 0.77 (95% CI= 0.76-0.77). Median OS and the hazard ratios by the three- and four- prognostic risk groups are presented in the table.
Conclusions:
CG model identified novel ctDNA PGAs prognostic of OS and can be utilized to classify patients into risk groups useful in selecting patients in future trials of mCRPC. Clinical trial information: NCT01949337.
Median OS and hazard ratios by the three- and four-prognostic risk groups.
Prognostic Risk Groups*
Median Overall Survival (95% Confidence Interval (CI)), months
Hazard Ratio (95% CI)
3-Prognostic Risk Groups
Low
Intermediate
Poor
58.9 (50.1- NR)
35.5 (32.3- 40.2)
19.3 (17.3- 21.5)
0.22 (0.17- 0.27)
0.42 (0.35- 0.51)
Reference
4-Prognostic Risk Groups
Low
Low Intermediate
Intermediate Poor
Poor
64.2 (52.8- NR)
43.6 (38.2- 48.9)
31.1 (28.3- 33.6)
17.0 (16.0- 18.9)
0.15 (0.11- 0.19)
0.26 (0.20- 0.33)
0.43 (0.34- 0.53)
Reference
*Patients classified into prognostic risk groups based on the tertile or the quartile of the predicted risk.
Clinical status
Clinical
1 clinical trial
25 organizations
2 drugs
14 targets
Organization
Duke University School of MedicineOrganization
Duke University Medical CenterOrganization
University of MinnesotaOrganization
Dana-Farber Cancer InstituteOrganization
University of Minnesota Masonic Cancer CenterOrganization
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USAOrganization
Genitourinary Oncology ServiceOrganization
Memorial Sloan Kettering Cancer CenterOrganization
Mount Sinai School of MedicineOrganization
Prostate Cancer FoundationOrganization
Department of Medical Oncology and UrologyOrganization
Thomas Jefferson UniversityOrganization
Helen Diller Family Comprehensive Cancer CenterOrganization
University of California IrvineOrganization
San Francisco Medical CenterOrganization
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer CenterOrganization
Department of Medical Oncology and Urology, Sidney Kimmel Medical College, Thomas Jefferson UniversityOrganization
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CAOrganization
Cancer Institute Center for Prostate and Urologic Cancer, Duke University Medical CenterDrug
enzalutamideDrug
abirateroneTarget
ARTarget
MYCTarget
MSH6Target
NKX3-1Target
BRCA2Target
PTENTarget
RB1Target
TP53Target
CHD1Target
ZBTB16Target
FANCATarget
RSPO2Target
PPP2R2ATarget
APCClinical trial
Phase III Trial of Enzalutamide (NSC# 766085) Versus Enzalutamide, Abiraterone and Prednisone for Castration Resistant Metastatic Prostate CancerStatus: Active (not recruiting), Estimated PCD: 2018-11-02