LBA 1 - Two Years of Anti-Androgen Treatment Increases Other-Cause Mortality in Men Receiving Early Salvage Radiotherapy: A Secondary Analysis of the NRG Oncology/RTOG 9601 Randomized Phase III Trial

D. E. Spratt1, R. T. Dess1, J. A. Efstathiou2, A. L. Zietman3, D. G. Wallington4, N. K. Jairath5, W. C. Jackson1, R. B. Den6,7, B. J. Stish8, T. M. Morgan9, J. J. Dignam10, T. M. Pisansky8, S. A. Rosenthal11, J. M. Michalski12, O. Sartor13, F. Y. Feng14, M. Schipper15, H. M. Sandler16, Y. Sun17, and W. U. Shipley2; 1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA,3Massachusetts General Hospital, Boston, MA, 4Western Michigan, Ann Arbor, MI, 5University of Michigan, Ann Arbor, MI,6Dept of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 7Thomas Jefferson, Philidelphia, PA, 8Department of Radiation Oncology, Mayo Clinic, Rochester, MN,9Department of Urology, University of Michigan, Ann Arbor, MI, 10University of Chicago, Department of Public Health Sciences, Chicago, IL, 11Sutter Medical Group and Cancer Center, Sacramento, CA, 12Washington University School of Medicine, St. Louis, MO, 13Tulane University, New Orleans, LA, 14Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 15Michigan Medicine, Department of Radiation Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, 16Cedars Sinai Medical Center, Los Angeles, CA, 17Department of Biostatistics, University of Michigan, Ann Arbor, MI

Purpose/Objective(s):

Salvage radiation therapy (SRT) is recommended for men with biochemically recurrent prostate cancer post-radical prostatectomy. RTOG 9601 was a randomized phase 3 clinical trial that demonstrated an overall survival (OS) benefit from the addition of long-term anti-androgen therapy to SRT. However, hormone therapy has well documented side effects and has been shown to increase cardiac event rates, and there remains no evidence of an OS benefit from hormone therapy for men treated with early SRT. Herein, we aim to determine if pre-SRT PSA can serve as both a prognostic and predictive biomarker of benefit or harm from hormone therapy.

Materials/Methods:

A secondary analysis of the NRG Oncology/RTOG 9601 double-blind, placebo-controlled randomized trial was conducted (NCT00002874). Patients were treated between 1998-2003 at over 100 centers across North America. Men with adverse pathology (positive surgical margin or pathologic T3 disease) and a PSA of 0.2-4.0 ng/mL were enrolled. Patients were stratified by entry PSA (0.2-1.5 vs >1.5-4.0 ng/mL). Men were randomized to either SRT plus a nonsteroidal anti-androgen (bicalutamide 150mg/day) or placebo for two years. The primary endpoint was OS. Secondary endpoints relevant to the present analysis include distant metastasis (DM) and other-cause mortality (OCM). Subgroup analyses were performed using the pre-specified PSA stratification variable (1.5 ng/mL) including tests for interaction. Competing risk analyses were performed for DM and OCM.

Results:

Of 760 patients, 85% (n=642/760) were in the pre-SRT PSA of ≤1.5 ng/mL stratum. There was no significant OS benefit with bicalutamide in men with PSA ≤1.5 ng/mL (HR 0.87 [95%CI 0.66-1.16]), whereas in men with PSA >1.5 ng/mL (n=118) OS was significantly improved (HR 0.45 [0.25-0.81]). Interaction test of PSA and hormone therapy benefit for OS was significant (p=0.02). Within the PSA ≤1.5 ng/mL subgroup, men with pre-SRT PSA ≤0.6 ng/mL (n=389) had increased OCM (sHR:1.94, [1.17-3.20]) from bicalutamide which was greatest in men with PSA 0.2-0.3 (n=148; sHR:4.14 [1.57-10.89]). There was also increased grade 3-5 cardiac events in those treated on the bicalutamide arm (p=0.04). The present subgroup analysis met 8 of 10 criteria for the reliability and credibility of this subgroup analysis.

Conclusion:

Pre-SRT PSA is both a prognostic and true predictive biomarker for benefit of hormone therapy with SRT. Long-term anti-androgen therapy did not improve OS in patients receiving early SRT, and may increase OCM. Ongoing trials are enrolling to identify which patients receiving early SRT will benefit from hormone therapy (NRG GU006, NCT03371719).

Author Disclosure: D.E. Spratt: None. R.T. Dess: None. J.A. Efstathiou: Joint Safety Review Committee; Bayer Healthcare. Consultant; Blue Earth Diagnostics, Taris Biomedical. Advisory Board; Bayer Healthcare, Genentech, Blue Earth Diagnostics, EMD Serono/Pfizer, Janssen. Co-chair; NRG Oncology, NCI. Vice-Chair; NRG Oncology. Member; NRG Oncology. Board of Directors; Massachusetts Prostate Cancer Coalition. GU Track Past-Chair; ASTRO. A.L. Zietman: Independent Contractor; Elsevier. D.G. Wallington: None. N.K. Jairath: None. R.B. Den: Research Grant; GenomeDx. Speaker's Bureau; Bayer. Advisory Board; GenomeDx, Bayer. B.J. Stish: None. J.J. Dignam: Independent Contractor; Merck. T.M. Pisansky: Member; NRG Oncology. S.A. Rosenthal: Chair, ACR Commission on Radiation Oncology; American College of Radiology (ACR). J.M. Michalski: Independent Contractor; Sheila Michalski and Associates. Research Grant; NCI. https://medicine.wustl.edu/news/effort-improve-radiation-therapy-veterans-receives-nearly-4-million/; Veteran's Administration. Consultant; Veteran's Administration. Speaker's Bureau; Boston Scientific, Inc. Advisory Board; Boston Scientific, Inc, Merck inc. Stock; ViewRay Inc. Chair Radiation Oncology Committee; NRG Oncology. Radiation Oncology Practice Assessment; Veterans Affairs. Co-chair GU Steering Committee; NCI. O. Sartor: Independent Contractor; FINO. Research Grant; Algeta, Bayer, Endocyte, Johnson & Johnson, Sanofi, Sotio. Consultant; Algeta, Astellas, Bavarian-Nordic, Bayer, Bellicum, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai. Travel Expenses; Algeta, Bayer, Sanofi. Stock; GSK, JNJ, Lilly. GU Committee Medical Oncology Chair; RTOG. F.Y. Feng: Research Grant; GenomeDx. Advisory Board; GenomeDx, Dendreon, Sanofi, Janssen, Firmagon, Astellas, Bayer. Travel Expenses; GenomeDx. Chair, GU Cancer Committee; Radiation Therapy Oncology Group. H.M. Sandler: Stock; Advanced Medical Isotope Corporation. Y. Sun: None. W.U. Shipley: Stock; Pfizer. Co-Chair of RTOG FOUNDATION; also Co-Chair of GU D; RTOG.