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The standard of care for patients with localized prostate cancer is radical prostatectomy (RP) but no recommendations exist for patients with persistently elevated prostate-specific antigen (PSA) after RP. The aim of this trial was to compare immediate salvage radiation therapy (iSRT) with or without short-term androgen deprivation therapy (ADT) in these patients and to select the most effective arm.

RP patients with non metastatic PCa on conventional preoperative imaging, and with a post-RP PSA level between 0.2 and 2 ng/mL were randomized (1:1) to iSRT alone (iSRT arm) or 6 months of ADT (degarelix) with iSRT (iSRT+ADT arm). ISRT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Biochemical progression-free survival (bPFS), metastates-free survival (MFS), overall survival (OS), quality of life, and toxicities were evaluated as secondary endpoints. With a pick the winner design, 122 pts were required to select the most effective arm with the probability > 80% (82% according to Liu's formula) for a 20% reduction in the instantaneous risk ratio (HR=0.80)

From Jan-2013 to Sept-2015, 125 pts were included (iSRT arm: 64 pts; iSRT+ADT arm: 61). Median follow up was 74.94 months (95% CI: 74.1-76.6). Median PSA was 0.6 ng/mL (0.12-3.65) at randomization. At 5 years. EFS rate was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 63.5% (95% CI: 49.9-74.2) in iSRT+ADT arm (HR=0.83; 95%CI: 0.47-1.47; p=0.528). bPFS rate was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 66% (95% CI: 52.3-76.6) in iSRT+ADT arm (HR=0.76; 95%CI: 0.44-1.31; p=0.322). MFS was in favor of the iSRT+ADT arm with HR=0.51 (95% CI: 0.26-0.99; p=0.048). OS data were not mature at the time of analysis. In a multivariate analysis, PSA level <0.6 ng/ml at randomization and tumor ≤pT3a were were significant good prognostic factors for bPFS (HR=0.56; 95%CI: 0.31-1.01; p=0.05 and HR=0.33; 95%CI: 0.19-0.58; p=0.0002, respectively). ISRT alone and PSA level <0.6 ng/ml at randomization were good prognostic factors for MFS (HR=0.39; 95%CI: 0.16-0.93; p=0.03 and HR=0.36; 95%CI: 0.14-0.88; p=0.019, respectively) in multivariate analysis. No grade 4 toxicities were observed. Overall, no difference in acute toxicity were observed between the 2 arms and more late toxicities (≥6 months after iSRT) were observed in the iSRT+ADT than the iSRT arm (53.1% vs 70.5%; p=0.046). At 12 months ADT-related symptoms were more important in the iSRT+ADT arm (QLQ-PR25; p=0.04). At 24 months, no difference in QLQ-C30 or QLQ-PR25 analysis was reported. After an initial 25-fold decrease in blood testosterone level, all patients recovered to normal level 12 months after starting ADT

This study demonstrated that iSRT+ADT is the most effective arm and improved MFS with good tolerance for patients with persistently elevated PSA after RP. iSRT+ADT may be used as reference arm for a phase III study.