Prostate-Specific Membrane Antigen PET-Guided Intensification of Salvage Radiotherapy After Radical Prostatectomy: A Phase 2 Randomized Clinical Trial.

Importance Prostate-specific membrane antigen positron emission tomography (PSMA-PET) offers superior accuracy in detecting prostate cancer lesions leading to intensified radiotherapy (RT), but its impact on patient outcomes is still undefined. Objective To evaluate whether intensification of salvage RT (SRT) after radical prostatectomy (RP) guided by PSMA-PET (PSMAiSRT) is associated with improved failure-free survival (FFS). Design, Setting, and Participants PSMAiSRT was a stratified cohort within a larger PSMA-guided intensification of radiotherapy (PSMAgRT) trial, a phase 2, two-center, registry-based randomized clinical trial. Patients with biochemical recurrence following RP who were eligible for standard-of-care (SOC) SRT from May 2018 to February 2021, were eligible for randomization in the PSMAiSRT stratum. A total of 130 patients were randomized, with 2 who did not proceed to radiotherapy (RT). The cutoff date for the primary analysis was October 26, 2023. Intervention Patients were randomized in a 1:1 ratio to receive either SOC SRT to the prostate bed, with or without elective pelvic RT, with or without adjuvant hormonal therapy (HT), or PSMA-PET/CT-guided SRT, intensified to detected sites of disease. Main outcome and measures The primary end point was FFS, defined as PSA progression (PSA nadir >0.2 ng/mL), radiological progression, next-line therapy initiation, or death. Results Among 128 patients (median [IQR] age, 71 [64-74] years), median (range) PSA at enrollment was 0.3 (0.1-3.0) ng/mL. In the PSMAiSRT group, 33 of 64 patients (52%) received intensified SRT; with addition of pelvic RT (n = 16 [25%]), metastasis-directed RT (n = 2 [3%]), lymph node boost (n = 19 [30%]), or prostate bed boost (n = 15). Adjuvant hormone therapy was equally prevalent in both arms (55 [86%] control vs 54 [84%] PSMAiSRT). At a median (range) follow-up of 37 (7-60) months, PSMAiSRT improved FFS (hazard ratio [HR], 0.50; 95% CI, 0.27-0.94; P = .04) and eugonadal FFS (HR, 0.45; 95% CI, 0.21-0.96; P = .03), with its greatest benefit in the subgroup with PSA of 0.3 ng/mL or more (HR, 0.17; 95% CI, 0.04-0.79; P = .01). Fewer next-line treatment events occurred in the PSMAiSRT arm (4 vs 12; HR, 0.32; 95% CI, 0.11-1.02; P = .04). There were no significant differences in toxic effects or quality of life between arms. Conclusion and Relevance This phase 2 trial demonstrated an isotoxic improvement in cancer control with PSMA-PET-guided intensification of SRT after RP. Confirmatory evidence is awaited from a subsequently accrued phase 3 trial. Trial Registration ClinicalTrials.gov NCT03525288.