Stereotactic Ablative Radiotherapy (SABR/SBRT) vs Observation for Recurrent Hormone-Sensitive Oligometastatic Prostate Cancer: Progression-Free Survival, Toxicity, Local Control, and PSMA PET Findings in the ORIOLE Phase 2 Randomized Clinical Trial

Abstract

Importance: Complete metastasis-directed ablation for oligometastatic prostate cancer may be an alternative to early androgen deprivation therapy (ADT). Objective: To determine whether stereotactic ablative radiotherapy (SABR), also termed stereotactic body radiotherapy (SBRT), improves oncologic outcomes in men with oligometastatic prostate cancer. Design, setting, and participants: The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized clinical trial accrued participants at 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018; the data cutoff for analysis was May 20, 2019. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detected by conventional imaging, who had not received ADT within 6 months of enrollment or for 3 or more years total, were randomized. Interventions: Patients were randomized 2:1 to receive SABR to metastases or observation. Main outcomes and measures: The primary outcome was progression at 6 months, defined by prostate-specific antigen level increase, progression on conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Prespecified secondary outcomes were SABR toxic effects, 6-month local control with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography for metastatic disease identification. Results: Among 54 randomized men, the median (range) age was 68 (61-70) years in the SABR group and 68 (64-76) years in the observation group. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease reduced the risk of new lesions at 6 months (16% vs 63%; P = .006). No grade 3 or greater toxic effects were observed. T-cell receptor sequencing showed significantly increased clonotypic expansion after SABR and a correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03). Conclusions and relevance: In oligometastatic prostate cancer, SABR improved outcomes, and benefit was enhanced by total consolidation of disease identified with PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict benefit from SABR. These findings support prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Trial registration: ClinicalTrials.gov Identifier: NCT02680587.