Survival Benefit of Adding Antiandrogen Therapy to Radiation in Recurrent Prostate Cancer: Final Results of RTOG 9601

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As reported in The New England Journal of Medicine by W.U. Shipley, MD, of Massachusetts General Hospital and Harvard Medical School, and colleagues in the NRG Oncology Radiation Therapy Oncology Group (RTOG), the final analysis of the phase III RTOG 9601 trial shows that the addition of antiandrogen therapy with bicalutamide to radiation therapy significantly improves overall and prostate cancer–specific survival in men with recurrent prostate cancer.1 Since the inception of the trial, bicalutamide has been replaced by the use of injectable gonadotropin-releasing hormone agonists in this setting.

Study Details

In the double-blind trial, 760 patients from NRG Oncology member sites, including community-based sites, were randomized between 1998 and 2003 to receive antiandrogen therapy consisting of 24 months of bicalutamide at 150 mg daily (n = 384) or daily placebo (n = 376) during and after radiation therapy. Patients had undergone prostatectomy with lymphadenectomy and had disease on pathologic testing consisting of tumor stage T2 (confined to the prostate but with a positive surgical margin) or T3 (histologic extension beyond the prostatic capsule), no nodal involvement, and prostate-specific antigen (PSA) level of 0.2 to 4.0 ng/mL. Radiation therapy consisted of two- or three-dimensional planning systems, according to institutional choice, and a total dose of 64.8 Gy, given in 36 daily fractions of 1.8 Gy in 5 sessions per week. The primary endpoint was overall survival.

Patients had a median age of 65 years, a median PSA level at baseline of 0.6 ng/mL, a median interval between surgery and first detectable prostate-specific antigen level of 1.4 years, and a median interval between surgery and trial entry of 2.1 years.

Improved Outcomes in Antiandrogen Group

Median follow-up among surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group vs 71.3% in the placebo group (hazard ratio [HR] = 0.77, P = .04). The 12-year prostate cancer–specific mortality rate on central review was 5.8% vs 13.4% (HR = 0.49, P < .001). The cumulative incidence of distant metastases at 12 years was 14.5% vs 23.0% (HR = 0.63, P = .005). The cumulative incidence of a second biochemical recurrence at 12 years was 44.0% vs 67.9% (HR = 0.48, P < .001). In a post hoc analysis, the bicalutamide group had a 55% improvement in overall survival at 12 years among patients with a PSA level > 1.5 ng/mL at study entry (HR = 0.45, P = .007).

The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival.….
— W.U. Shipley, MD, and colleagues

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In subgroup analyses, hazard ratios for overall survival favored bicalutamide, according to Gleason score (significant for score of 7; HR = 0.69, P = .04), PSA levels of 0.7 to 1.5 ng/mL (HR = 0.61, P = .03) or > 1.5 ng/mL, and positive or negative surgical margin (significant for positive margin; HR = 0.73, P = .04). The hazard ratio nonsignificantly favored placebo among patients with a baseline PSA level < 0.7 ng/mL (HR = 1.13, P = .53).

On multivariate analysis, the bicalutamide treatment group (HR = 0.75, P = .025), entry PSA level of 1.6 to 4.0 ng/mL vs 0.2 to 1.5 ng/mL (HR = 1.59, P = .003), age ≥ 65 years vs < 65 years (HR = 2.18, P < .001), and Gleason score of 8 to 10 vs 2 to 6 (HR = 1.89, P < .001) were significantly associated with overall survival.

Adverse Events

Grade 1, 2, and 3 hot flashes in the bicalutamide vs placebo groups occurred in 16.6% vs 14.1%, 4.5% vs 2.9%, and 0.8% vs 0% of patients, respectively. Gynecomastia occurred in 69.7% vs 10.9% of patients, including grade 1, 2, and 3 events in 42.4% vs 8.8%, 23.6% vs 2.1%, and 3.7% vs 0% (P < .01 for all). Among late toxicities, grade 3 genitourinary adverse events occurred in 7.0% vs 6.0%, and grade 4 genitourinary events occurred in 0.3% and 0.8%; grade 2 liver toxicity occurred in 1.6% vs 0.8%, and grade 3 liver toxicity in 0.8% vs 0.3%.

The investigators concluded: “The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo.” ■

Disclosure: For full disclosures of the study authors, visit


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.

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