A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013).
4514 Background: Intermittent androgen suppression (IAS) for PSA recurrence after radical radiotherapy (RT) may improve quality of life (QoL) and delay hormone resistance (HR) but has an unknown effect on survival. We compared overall survival (OS) for IAS vs. continuous androgen deprivation (CAD) in an open label, non-inferiority randomized trial. Methods: Eligible patients had rising PSA > 3.0 ng/ml >1 year post radical or salvage RT +/- up to 1 year of neo/adjuvant androgen deprivation therapy (ADT) for localized prostate cancer. Stratification factors were time since RT (>1-3 vs. >3 years), initial PSA (15), and prior radical prostatectomy or ADT. IAS cycles were 8 months treatment with PSA-determined off-treatment periods. Primary endpoint was OS. Secondary: QoL, HR, cholesterol/HDL/LDL, length of non-treatment periods, testosterone and potency recovery. The study closed when the p-value for non-inferiority in a planned interim analysis was < a pre-specified stopping threshold. Results: 690 patients were randomized to IAS ; 696 to CAD. Median age was 74.2 years; follow up 6.9 years. Baseline factors were balanced. IAS patients completed 1-9 8-month cycles (median:2) and had reduced hot flashes but no differences in other AEs, including myocardial events or osteoporotic fractures. 35% of IAS cases had full testosterone recovery. Cross sectional QOL analysis shows a range of benefits for IAS at varying times. Using a 10 point change from baseline score as clinically meaningful, IAS patients had better QoL in physical function (p < 0.01), fatigue (p < 0.01), urinary problems (p = 0.01), hot flashes (p < 0.01), desire for sexual activity (p < 0.01) and erectile function (p < 0.01). 524 patients died (268 IAS vs. 256 CAD). Median OS was 8.8 vs. 9.1 years on IAS and CAD arms respectively (HR 1.02, 95%CI = 0.86-1.21; p for non-inferiority [HR IAS vs. CAD ≥ 1.25] = 0.009). IAS arm had more disease related (122 vs. 97) and fewer unrelated (134 vs. 146) deaths. Time to HR was statistically significantly improved on the IAS arm (HR 0.80, 95CI 0.67-0.98, p=0.024). Conclusions: IAS is non-inferior to CAD with respect to OS.