Philip W. Kantoff, MD
Daniel E. Spratt, MD
Edoardo Francini, MD
The recent report of results of RTOG 9601 by Shipley et al in The New England Journal of Medicine1—reviewed in this issue of The ASCO Post—strongly supports the variably used practice of adding “androgen blockade” to salvage radiation therapy in men with a rising prostate-specific antigen (PSA) after radical prostatectomy. The findings show a clear reduction in prostate cancer–specific and overall mortality with the addition of 2 years of bicalutamide to salvage radiation therapy. Another likely (although not demonstrated) benefit is the reduction in the need to treat patients with subsequent life-long continuous or intermittent androgen blockade at the expense of treating all men with 2 years of bicalutamide.
RTOG 9601’s results further strengthen the growing concept that inhibition of androgen signaling can work in synergy with radiotherapy by inhibiting DNA repair and functioning as a potent radiosensitizer.2,3 These data are consistent with the large number of trials in intermediate- and high-risk localized prostate cancer in which the addition of androgen suppression to radiotherapy improved overall survival.4,5 However, one should be cautious about extrapolating all methods of androgen blockade as equal, as one of the only trials of radiotherapy in localized prostate cancer that did not show a benefit from androgen blockade was when bicalutamide monotherapy was used.6
Evolution of Androgen Blockade
The authors appropriately point out that androgen blockade has evolved since the conception of this trial wherein bicalutamide was used. Bicalutamide is a relatively weak androgen receptor antagonist and has been shown to have agonist properties as well.7 One can surmise that bicalutamide was used instead of a gonadotropin-releasing hormone (GnRH) agonist in this study (a standard form of androgen blockade then and now), to try to reduce treatment-related side effects. However, a meta-analysis has shown the superiority of GnRH analogs to bicalutamide, and they would be considered today a standard form of androgen blockade.8
Thus, the authors point out that the use of bicalutamide should be viewed as a proof of principle that earlier androgen blockade with salvage radiation therapy leads to improved survival over delayed androgen blockade. However, we do not know yet what constitutes optimal therapy for these patients, specifically regarding the type (eg, bicalutamide, second-generation antiandrogens, GnRH analogs) or the duration of androgen blockade (eg, 6 months, 2 years, life-long).
Other Clinical Trials
Early data have recently been published from the GETUG-AFU-16 trial, which randomly assigned men to standard salvage radiation therapy or salvage radiation therapy plus short-term androgen blockade with 6 months of goserelin (Zoladex).9 Patients assigned to salvage radiation therapy plus goserelin were significantly more likely than patients who received salvage radiation therapy alone to be free of biochemical disease progression or clinical disease progression at 5 years (80% vs 62%, hazard ratio = 0.50, P < .0001), and the greatest benefit was found in men with a higher presalvage radiation therapy PSA level.9 Given the relatively short follow-up of 5 years, survival data are not yet available.
One should be cautious about extrapolating all methods of androgen blockade as equal….— Philip W. Kantoff, MD, Daniel E. Spratt, MD, and Edoardo Francini, MD
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Other studies are ongoing that will help elucidate the timing of postoperative radiation therapy and the duration of androgen blockade. The Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS, ClinicalTrials.gov identifier NCT00541047) study, which closed to accrual in December 2016, is designed to compare the use of adjuvant radiation therapy with early salvage radiation therapy postradical prostatectomy and whether 2 years or 6 months of androgen blockade is superior. Maturation of these trials will help provide insight into the preferred treatment approach postoperatively.
Observations and Questions
More broadly, the Shipley et al article allows us to make some observations about this population and raises many questions. First, the readout of this study “20 years after conception” and with a median follow-up of 13 years begs the need for an intermediate clinical endpoint short of overall or prostate cancer–specific survival, such as metastasis-free survival or potentially freedom from PSA failure. This is particularly poignant when the therapies used in studies designed years ago are no longer relevant to current practice.
Second, not surprisingly, the prostate cancer–specific mortality, even after 13 years of follow-up, remains low (13.4% vs 5.8%), highlighting the need for patient selection based on clinical factors and possibly heretofore undetermined molecular biomarkers to reduce the number treated to benefit.
Finally, it is interesting to note a lack of benefit in distant metastases or overall survival in more “favorable-risk” patients in this study, primarily men with a PSA level < 0.7 ng/mL and a Gleason score < 7. As shown in their multivariable analysis, patients with a low presalvage radiation therapy PSA level had a better prognosis than those with a higher presalvage radiation therapy PSA level, and thus a paucity of events in these more favorable-risk patients. Given the substantial benefit in patients with higher presalvage radiation therapy PSA levels, an indicator of a greater likelihood of micrometastatic disease, it makes one wonder whether the beneficial effect in higher-risk patients is largely due to the suppression of growth of micrometastases. This is particularly promising, since it may indicate that a relatively weak agent, such as bicalutamide, could have such a large relative effect on outcomes. This leads us to ponder whether the use of more effective agents that inhibit androgen signaling may have a more profound effect and might be curative in this context. ■
Dr. Kantoff is Chairman of Medicine, Memorial Sloan Kettering Cancer Center, New York, and Professor of Medicine, Weill Cornell Medical College; Dr. Spratt is Assistant Professor, Radiation Oncology, University of Michigan, Ann Arbor; and Dr. Francini is a research fellow, Dana-Farber Cancer Institute, Boston.
Disclosure: Drs. Kantoff, Spratt, and Francini reported no conflicts of interest.
References
1. 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.
2. Polkinghorn WR, Parker JS, Lee MX, et al: Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 3:1245-1253, 2013.
3. Spratt DE, Evans MJ, Davis BJ, et al: Androgen receptor upregulation mediates radioresistance after ionizing radiation. Cancer Res 75:4688-4696, 2015.
4. D’Amico AV, Chen MH, Renshaw A, et al: Long-term follow-up of a randomized trial of radiation with or without androgen deprivation therapy for localized prostate cancer. JAMA 314:1291-1293, 2015.
5. Jones CU, Hunt D, McGowan DG, et al: Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 365:107-118, 2011.
6. McPartlin AJ, Glicksman R, Pintilie M, et al: PMH 9907: Long-term outcomes of a randomized phase 3 study of short-term bicalutamide hormone therapy and dose-escalated external-beam radiation therapy for localized prostate cancer. Cancer 122:2595-2603, 2016.
7. Culig Z, Hoffmann J, Erdel M, et al: Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 81:242-251, 1999.
8. Kunath F, Grobe HR, Rücker G, et al: Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: A Cochrane systematic review. BJU Int 116:30-36, 2015.
9. 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-AFU 16): A randomised, multicentre, open-label phase 3 trial. Lancet Oncol 17:747-756, 2016.
