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SAN FRANCISCO -- Anti-androgen therapy using daily bicalutamide improved overall survival modestly among men with high-risk prostate cancer who received salvage radiotherapy after radical prostatectomy.

Men randomized to daily bicalutamide for 24 months in the clinical trial had 10-year overall survival of 82% versus 78% in the placebo arm (hazard ratio 0.77, 95% CI 0.59-0.99, P=0.04). The bicalutamide group also had reduced rates of metastatic prostate cancer and death from prostate cancer, , reported here at the Genitourinary Cancers Symposium.

"Treatment was tolerated quite well and with a high completion rate, not only for radiotherapy but the daily pills for 2 years," said Shipley, of Massachusetts General Hospital in Boston.

From March 1998 to March 2003, 760 patients with high-risk prostate cancer were randomized to receive radiotherapy (64.8 Gy) plus bicalutamide or placebo. Eligible patients had stage pT3 N₀ or pT2 N₀ disease with positive margins, elevated prostate-specific antigen (PSA) to a maximum of 4.0 ng/mL, and negative abdominal/pelvic findings on computed tomography and bone scans.

The the cohort had a median age of 65, positive margins in 75%, median entry PSA of 0.6 ng/mL and their median interval between radical prostatectomy and first detectable PSA of 1.4 years.

Shipley reported that 97% in the anti-androgen arm and 95% in the placebo arm completed their radiation protocols, and 84% and 93%, respectively, completed taking their daily oral tablets. The primary reason for not completing daily bicalutamide was gynecomastia. He said that 70% of patients randomized to bicalutamide had some degree of gynecomastia.

The incidence of metastatic prostate cancer was reduced from 19% in the placebo arm to 11% in the bicalutamide arm (HR 0.63, 95% CI 0.46-0.87, P=0.005).

Death from prostate cancer occurred in 4.5% of patients randomized to anti-androgen therapy compared with 10.1% of those randomized to placebo (HR 0.49, 95% CI 0.32-0.74, P<0.001). "The number needed to treat to save one man from dying of prostate cancer is 12," said Shipley. "It's quite low."

Multivariable analysis for overall survival revealed that treatment with anti-androgen therapy was a significant predictor of improved survival (P=0.025), and study entry PSA ≤1.5 ng/mL (P=0.003), age ≥65 years (P<0.001) and Gleason score 8 to 10 (P<0.001) were significant predictors of worse overall survival.

Anti-androgen therapy demonstrated significant benefit on major endpoints in several subgroups.

• Among men with entry PSA level >1.5 ng/mL, anti-androgen therapy was associated with an HR of 0.45 (95% CI 0.25-0.81, P=0.007) for overall survival and an HR of 0.36 (95% CI 0.15-0.84, P=0.014) for time to metastatic prostate cancer
• In the subgroup of men with Gleason grade 7 disease, anti-androgen therapy was associated with an HR of 0.69 (95% CI 0.49-0.98, P=0.039) for overall survival
• Among men with positive surgical margins, anti-androgen therapy was associated with an HR of 0.87 (95% CI 0.53-1.41, P=0.038) for overall survival and an HR of 0.56 (95% CI 0.38-0.84, P=0.005) for time to metastatic prostate cancer
• In the subgroup with Gleason grade 8 to 10, the time to metastatic prostate cancer was improved with anti-androgen therapy (HR 0.35, 95% CI 0.18-0.67, P=0.001)

The incidences of late genitourinary (GU) and gastrointestinal (GI) toxicity were not different between the two arms. GU ≥grade 2 toxicity occurred in 32% of each arm and GU ≥grade 3 toxicity occurred in 7% of each arm. The rates of GI ≥grade 2 toxicity were 20% in the anti-androgen arm and 16% in the placebo arm, and the rates of GI ≥grade 3 toxicity were 3% and 2%, respectively.

The RTOG 9601 trial expands the established role of androgen deprivation therapy with radiation therapy in high-risk prostate cancer to now include patients who have previously had surgery, said discussant , of the Texas Center for Proton Therapy in Irving. "This is the first Level I evidence looking at the addition of hormonal therapy to radiotherapy for patients who've undergone radical prostatectomy," he said. "This is a treatment that has a 'wow' impact."

The optimal duration of anti-androgen therapy in this setting is unknown, said Hamstra. A three-arm trial known as RADICALS being conducted in Great Britain may provide an answer; one arm of the trial is being randomized to 6 months of hormonal therapy plus radiotherapy after prostate surgery while another arm receives 2 years of hormonal therapy (the third arm is randomized to radiotherapy alone).