315 - Long-Term Transcriptomic Analysis of NRG/RTOG 9601: A Phase 3 Study of Salvage Radiotherapy for Prostate Cancer with or without Anti-Androgen Therapy
Presenter(s)
K. Patel1,2, E. Feng3, E. Walker4, J. Proudfoot5, E. Davicioni6, J. Simko7, H. M. Sandler8, A. Pollack9, J. A. Efstathiou10, A. P. Dicker11, D. E. Spratt12, J. P. Bahary13, H. Lukka14, W. A. Hall15, B. J. Stish16, W. Shi17, J. D. Pennington18, S. Pugh19, P. L. Nguyen20, and P. T. Tran21; 1Department of Radiation Oncology, National Cancer Institute, NIH, Bethesda, MD, 2The University of Texas MD Anderson Cancer Center, Houston, TX, 3Stanford University, Stanford, CA, 4Veracyte, Inc., San Diego, CA, 5Veracyte, San Diego, CA, 6Veracyte, Inc., South San Francisco, CA, 7UCSF, San Franscico, CA, 8Oregon Health and Science University, Portland, OR, 9Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, 10Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 11Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 12University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, 13CHUM, Montreal, QC, Canada, 14Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada, 15Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, 16Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 17Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 18Southeast Cancer Control Consortium, Inc., CCOP, Winston-Salem, NC, 19NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 20Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, 21Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s):
The prognostic utility of a genomic classifier (GC) on overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) after salvage radiotherapy (sRT) was previously validated in NRG/RTOG 9601, a phase 3 trial of sRT ± high-dose bicalutamide [anti-androgen therapy (AAT)]. A separate analysis of NRG/RTOG 9601 showed that AAT may increase cardiovascular mortality and that pre-sRT PSA was predictive of the benefit from AAT. Here, we update the prior work with final outcomes data from NRG/RTOG 9601 to characterize the clinical utility of modern clinico-transcriptomic risk stratification.Materials/Methods:
This is a secondary analysis of NRG/RTOG 9601 with GC scores (Veracyte; San Diego, CA) from a prior National Clinical Institute-translational science project. The primary objective was to estimate the prognostic impact of GC score (per 0.1) on PCSM, and secondarily on OS, metastasis-free survival (MFS), and DM. Additional objectives were the estimation of PCSM and OS by pre-defined GC strata [low (=0.4), intermediate (0.4-0.6), high (0.6-0.85), and very high (>0.85)] and the estimation of the PCSM benefit of AAT by GC (<0.6 vs =0.6) within pre-sRT PSA subgroup (<0.7 vs =0.7). PCSM was selected as the primary endpoint in this secondary analysis to evaluate disease-specific prognosis and AAT treatment effect, given the suggestion of increased other-cause mortality with high-dose bicalutamide, which may not occur with contemporary androgen deprivation therapy (ADT). Multivariable Cox or Fine-Gray models were fit and adjusted (subdistribution) hazard ratios [(s)HR] were reported with 95% confidence intervals.Results:
A total of 352 patients were included in the GC-available cohort with a median follow-up of 18.2 years. The median GC score was 0.59 (Q1-Q3: 0.42-0.76), and 29%, 23%, 38%, and 11% had low, intermediate, high, and very high GC risk scores, respectively. GC was independently prognostic for all profiled endpoints [sHRPCSM 1.34 (1.17-1.54); HROS 1.18 (1.09-1.27); HRMFS 1.16 (1.08-1.25); sHRDM 1.20 (1.07-1.35); all p=0.002]. Furthermore, there was a clinically meaningful difference in prognosis between the low and very high GC subgroup at 15 years: ?PCSM15-Year of 48% (4% vs. 52%) and ?OS15-Year of 50% (75% vs. 25%). Within the high pre-sRT PSA (=0.7) subgroup, the absolute improvement in 15 year PCSM with AAT was clinically meaningful across GC risk (GC<0.6: 12%; GC=0.6: 6%), whereas in the low pre-sRT PSA (<0.7) subgroup, only the high GC risk patients derived a clinically meaningful 15-year PCSM benefit (GC<0.6: -2%; GC=0.6: 16%). However, there was no significant interaction between GC and AAT effect within either PSA strata (both p>0.05) likely due to limited power.Conclusion:
With the long-term update of NRG/RTOG 9601, GC score continues to provide clinically meaningful prognostic information beyond clinical data. These analyses support the hypothesis that GC may have clinical utility in selecting early sRT candidates for modern ADT.