In a recent article in JAMA Oncology, reviewed in this issue of The ASCO Post, Dess et al present an important analysis to help guide decision-making in the setting of salvage radiotherapy in prostate cancer.1 This secondary analysis assessed the association of prostate-specific antigen (PSA) levels prior to radiotherapy with outcomes of long-term androgen-deprivation therapy (ADT) in men treated in the RTOG 9601 trial.
Designed more than 20 years ago, this seminal trial enrolled 760 men with biochemically recurrent prostate cancer who originally underwent radical prostatectomy with lymphadenectomy demonstrating positive surgical margins or T3 disease. Patients were also required to have a detectable PSA level ranging from 0.2 to 4 ng/mL, computed tomography and bone scan imaging showing no metastatic disease, adequate hepatic function, and life expectancy of more than 10 years. Men were randomly assigned to salvage radiotherapy with 2 years of bicalutamide or placebo.
Long-term results published in The New England Journal of Medicine in 2017 showed the 12-year overall survival was improved with the use of androgen-deprivation therapy from 71% to 76%, and the cumulative incidence of metastatic disease improved from 23% to 14.5%.2 Hypothesis-generating post hoc analysis suggested patients with a PSA level less than 0.7 ng/mL may have less benefit.
Benefit Based on PSA Level
Exploration of this hypothesis by Dess and colleagues indicated the overall survival benefit seen in RTOG 9601 was limited to patients with a PSA level of at least 0.6 ng/mL. Patients with a PSA level higher than 1.5 ng/mL had a 25% absolute benefit at 12 years. Of note, patients with a PSA level up to 0.6 ng/mL did not benefit from androgen-deprivation therapy but rather had a twofold increased risk of other-cause mortality and a threefold increased risk of high-grade cardiac and neurologic toxicities. The overall survival benefit with androgen-deprivation therapy was largely driven by a decrease in distant metastases, with a 66% reduction in the PSA level > 1.5 ng/mL stratum. The bicalutamide treatment effect varied with PSA level prior to salvage radiotherapy, demonstrating the level was a continuous variable.
The overall survival benefit seen in RTOG 9601 was limited to patients with a PSA level of at least 0.6 ng/mL.— Manuj Agarwal, MD
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Subgroup analyses may be subject to bias and can be underpowered. Although caution must be taken when reviewing an unplanned subgroup analysis, the authors rightfully point out that, at the time of the trial design, it was not common to include formalized subgroup statistical hypotheses. The analysis by Dess and colleagues meets all available criteria for credibility of a subgroup analysis.3
This report adds to the small but growing body of literature on the role of androgen-deprivation therapy in the postoperative setting. GETUG-AFU16 previously reported a progression-free survival benefit with the use of short-term ADT. This relatively contemporary phase III multicenter trial randomly assigned 743 men with a postoperative PSA level between 0.2 and 2 ng/mL to salvage radiotherapy, with or without 6 months of goserelin, and found an 18% absolute improvement in progression-free survival at 5 years.4 We await the final results of the phase III RTOG 0534 trial of salvage radiotherapy and short-term androgen-deprivation therapy, which thus far have been reported only in abstract form.5
Prognostic and Predictive Biomarker
Dess et al demonstrate that PSA levels prior to salvage radiotherapy may serve as a biomarker with prognostic and predictive value. It affords the opportunity to tailor the delivery of androgen-deprivation therapy in this setting to patients who may be most likely to benefit from it and to avoid therapy in men who are more likely to suffer from it. Although the use of bicalutamide has largely been replaced with gonadotropin-releasing hormone agonist treatment, available data suggest similar biologic efficacy,6 and results are likely to translate to a modern cohort of patients. It is not known whether this benefit can be extrapolated to shorter durations of androgen-deprivation therapy.
Dr. Agarwal is Assistant Professor of Radiation Oncology at the University of Pennsylvania and Medical Director of Radiation Oncology at the Abramson Cancer Center at Penn Presbyterian Medical Center, Philadelphia.
Publisher's Note: This article was originally published in the June 10, 2020 issue of The ASCO Post.
DISCLOSURE: Dr. Agarwal reported no conflicts of interest.
REFERENCES
1. Dess RT, Sun Y, Jackson WC, et al: Association of presalvage radiotherapy PSA levels after prostatectomy with outcomes of long-term antiandrogen therapy in men with prostate cancer. JAMA Oncol 6:1-9, 2020.
2. Shipley WU, Seiferheld W, Lukka HR, et al: Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med 376:417-428, 2017.
3. Sun X, Briel M, Busse JW, et al: Credibility of claims of subgroup effects in randomized controlled trials: Systematic review. BMJ 344:e1553, 2012.
4. Carrie C, Hasbini A, de Laroche G, et al: Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU16): A randomised, multicentre, open-label phase III trial. Lancet Oncol 17:747-756, 2016.
5. Pollack A, Karrison TG, Balogh Jr AG, et al: Short term androgen deprivation therapy without or with pelvic lymph node treatment added to prostate bed only salvage radiotherapy: The NRG Oncology/RTOG 0534 SPPORT trial. Int J Radiat Oncol Biol Phys 102:1605, 2018.
6. Wirth MP, See WA, McLeod DG, et al: Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: Results from the second analysis of the Early Prostate Cancer Program at median follow-up of 5.4 years. J Urol 172:1865-1870, 2004.
