Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kishan 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 personal fees from Janssen outside the submitted work. Dr Feng reported personal fees from Janssen, Sanofi, Blue Earth Diagnostics, Astellas, Clovis, Genentech, Bayer, and Celgene, nonfinancial support from PFS Genomics, Nutcracker Therapeutics, and Serimmune outside the submitted work. Dr Spratt reported personal fees from Janssen and personal fees from Blue Earth outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Overall Survival Outcomes by Presalvage Radiation Therapy Prostate-Specific Antigen (PSA)

HR indicates hazard ratio. Overall survival by presalvage radiotherapy PSA strata (A) and by treatment assignment for patients with PSA levels of 1.5 ng/mL or lower (B) and PSA levels higher than 1.5 ng/mL(C).

Figure 2.. Outcomes for Men at or Below the Median Presalvage Radiotherapy Prostate-Specific Antigen (PSA) Level of 0.60 ng/mL by Treatment Arm

HR indicates hazard ratio. A, Overall survival; B, cumulative incidence of distant metastasis; and C, other-cause mortality for patients at or below the median trial PSA levels by treatment arm.

Figure 3.. Forest Plot of Overall Survival, Distant Metastasis, and Other-Cause Mortality by Presalvage Radiotherapy PSA Level

HR indicates hazard ratio; PSA, prostate-specific antigen.