TY - JOUR
T1 - Association of Presalvage Radiotherapy PSA Levels after Prostatectomy with Outcomes of Long-Term Antiandrogen Therapy in Men with Prostate Cancer
AU - Dess, Robert T.
AU - Sun, Yilun
AU - Jackson, William C.
AU - Jairath, Neil K.
AU - Kishan, Amar U.
AU - Wallington, David G.
AU - Mahal, Brandon A.
AU - Stish, Bradley J.
AU - Zumsteg, Zachery S.
AU - Den, Robert B.
AU - Hall, William A.
AU - Gharzai, Laila A.
AU - Jaworski, Elizabeth M.
AU - Reichert, Zachary R.
AU - Morgan, Todd M.
AU - Mehra, Rohit
AU - Schaeffer, Edward M.
AU - Sartor, Oliver
AU - Nguyen, Paul L.
AU - Lee, William Robert
AU - Rosenthal, Seth A.
AU - Michalski, Jeff M.
AU - Schipper, Matthew J.
AU - Dignam, James J.
AU - Pisansky, Thomas M.
AU - Zietman, Anthony L.
AU - Sandler, Howard M.
AU - Efstathiou, Jason A.
AU - Feng, Felix Y.
AU - Shipley, William U.
AU - Spratt, Daniel E.
N1 - Funding Information:
This study is supported by the NCI Cancer Trials Support Unit (CTSU) [1/31/07]
Funding Information:
Additional Contributions: We thank the Prostate Cancer Foundation (DES), the Prostate Cancer NIH SPORE (DES, P50CA186786), and the Department of Defense (DES, PC151068). Additionally, we are thankful for the support of the NCI in conducting this randomized clinical trial, U10CA180868 (NRG Oncology Operations), and U10CA180822 (NRG Oncology Statistics and Data Management Center).
Funding Information:
received honoraria and consulting fees from Varian Medical Systems, Inc, ViewRay, Inc, and Intelligent Automation, Inc. Dr Kishan has also served on an advisory board for Janssen, Inc, and received research funding from the Prostate Cancer Foundation. Dr Zumsteg reported personal fees from EMD Serono and Scripps Proton Therapy Center outside the submitted work. Dr Den reported grants from GenomeDx during the conduct of the study and personal fees from Alpha Tau outside the submitted work. Dr Hall reported institutional research support from Elekta AB, Stockholm, Sweden outside the submitted work. Dr Sartor reported personal fees from Advanced Accelerator Applications and Astellas; grants and personal fees from AstraZeneca and Bayer; personal fees from Bellicum, Blue Earth Diagnostics, Inc; personal fees from Bravarin Nordic, Bristol Myers Squibb, Clovis, and Constellation; grants and personal fees from Dendreon, personal fees from EMD Serono, personal fees from Myriad, personal fees from Noxopharm, personal fees from Progenics, grants and personal fees from Jennsen, personal fees from Myovant, personal fees from Pfizer, grants and personal fees from Sanofi, grants from Endocyte, Innocrin, Invitae, and SOTIO outside the submitted work; in addition, Dr Sartor had a patent to 7 166 691 issued and licensed. Dr Nguyen reported grants and personal fees from Bayer, personal fees from Boston Scientific, grants and personal fees from Janssen, personal fees from Dendreon, personal fees from Ferring, personal fees from Cota, grants and personal fees from Astellas, personal fees from Blue Earth, and personal fees from Augmenix outside the submitted work. Dr Michalski reported grants from NCI funded RTOG/NRG grant during the conduct of the study; personal fees from Merck, inc; and personal fees from Boston Scientific, inc; outside the submitted work. Dr Zietman reported a stipend as editor in chief of International Journal of Radiation Oncology Biology Physics from Elsevier publishers. Dr Sandler reported personal fees from Janssen and stock interests in Radiogel outside the submitted work; and Former chair, NRG Oncology GU Cancer Committee Member, ASTRO Board of Directors. Dr Efstathiou reported personal fees from Blue Earth Diagnostics, Taris Biomedical, Boston Scientific, AstraZeneca, Bayer Healthcare, Genentech/Roche, and EMD Serono/Pfizer, and
Funding Information:
All patients initially consented to enroll on RTOG 9601 after local institutional review board approval. This secondary analysis was exempt from institutional review board approval because no identifying patient health information was shared between the National Cancer Institute and the University of Michigan. The trial protocol and analysis plan are available in Supplement 1. The RTOG 9601 trial was a double-blind, placebo-controlled trial of men receiving SRT with or without the addition of a nonsteroidal antiandrogen (150 mg/d bicalutamide for 2 years). All patients received SRT to the prostate bed (64.8 Gy in 1.8 Gy per fraction) only. The trial was sponsored by the National Cancer Institute and conducted through RTOG/NRG Oncology. AstraZeneca supplied drug/placebo, but had no role in collection of data, analysis, or preparation of any report. Approval for analysis was granted by NRG Oncology and the National Cancer Institute through a data-sharing agreement with the senior author (D.E.S.). Herein, antiandrogen
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/5
Y1 - 2020/5
N2 - Importance: In men with recurrent prostate cancer, addition of long-Term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. Objective: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Interventions: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. Design, Setting, and Participants: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Results: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P =.01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P =.05). Conclusions and Relevance: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-Term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT00002874.
AB - Importance: In men with recurrent prostate cancer, addition of long-Term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. Objective: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Interventions: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. Design, Setting, and Participants: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Results: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P =.01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P =.05). Conclusions and Relevance: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-Term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT00002874.
UR - http://www.scopus.com/inward/record.url?scp=85082524498&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2020.0109
DO - 10.1001/jamaoncol.2020.0109
M3 - Article
C2 - 32215583
AN - SCOPUS:85082524498
SN - 2374-2437
VL - 6
SP - 735
EP - 743
JO - JAMA oncology
JF - JAMA oncology
IS - 5
ER -