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.
To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT.
Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years.
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.
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).
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).
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.
ClinicalTrials.gov Identifier: NCT00002874.
JAMA oncology. 2020 Mar 26 [Epub ahead of print]
Robert T Dess, Yilun Sun, William C Jackson, Neil K Jairath, Amar U Kishan, David G Wallington, Brandon A Mahal, Bradley J Stish, Zachery S Zumsteg, Robert B Den, William A Hall, Laila A Gharzai, Elizabeth M Jaworski, Zachary R Reichert, Todd M Morgan, Rohit Mehra, Edward M Schaeffer, Oliver Sartor, Paul L Nguyen, William Robert Lee, Seth A Rosenthal, Jeff M Michalski, Matthew J Schipper, James J Dignam, Thomas M Pisansky, Anthony L Zietman, Howard M Sandler, Jason A Efstathiou, Felix Y Feng, William U Shipley, Daniel E Spratt
Department of Radiation Oncology, University of Michigan, Ann Arbor., Department of Radiation Oncology, University of California, Los Angeles., Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota., Department of Radiation Oncology, Cedars-Sinai Medical Center, West Hollywood, California., Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania., Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee., Department of Medicine, University of Michigan, Ann Arbor., Department of Urology, University of Michigan, Ann Arbor., Department of Pathology, University of Michigan, Ann Arbor., Department of Urology, Northwestern University, Chicago, Illinois., Department of Medicine, Tulane Cancer Center, New Orleans, Louisiana., Department of Radiation Oncology, Duke Health, Durham, North Carolina., Department of Radiation Oncology, Sutter Medical Group, Sacramento, California., Department of Radiation Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri., Department of Public Health Sciences, University of Chicago, Chicago, Illinois., Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts., Department of Radiation Oncology, University of California, San Francisco.