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.