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Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: the ORIOLE phase 2 randomized clinical trial

  • Ryan Phillips,
  • William Yue Shi,
  • Matthew Deek,
  • Noura Radwan,
  • Su Jin Lim,
  • Emmanuel S. Antonarakis,
  • Steven P. Rowe,
  • Ashley E. Ross,
  • Michael A. Gorin,
  • Curtiland Deville,
  • Stephen C. Greco,
  • Hailun Wang,
  • Samuel R. Denmeade,
  • Channing J. Paller,
  • Shirl Dipasquale,
  • Theodore L. DeWeese,
  • Daniel Y. Song,
  • Hao Wang,
  • Michael A. Carducci,
  • Kenneth J. Pienta,
  • Martin G. Pomper,
  • Adam P. Dicker,
  • Mario A. Eisenberger,
  • Ash A. Alizadeh,
  • Maximilian Diehn,
  • Phuoc T. Tran


Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).


To determine if stereotactic ablative radiotherapy (SABR) 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 study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.


Patients were randomized in a 2:1 ratio to receive SABR or observation.

Main Outcomes and Measures  

The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months 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 in the identification of metastatic disease.


In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with 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 decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).

Commented by Prof. Tsaur

The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) study is a randomized 2-arm phase 2 clinical trial set to determine if stereotactic ablative radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer (OMPC). The latter was defined as recurrent disease after initial curative treatment of the primary tumor by radical prostatectomy or radiotherapy with 1-3 metastases emerged in the last 6 mos. Enrollment as well as treatment fields relied on conventional imaging by CT-scan, MR and/or bone scan. Patients randomized to SABR were subjected to PSMA-PET-CT at baseline and day 180. 54 men were finally randomized in a 2:1 ratio to SABR or observation. The primary composite outcome of progression at 6 mos. included biochemical, radiographic and symptomatic progression, initiation of ADT or death.

With the median follow-up of 19 mos. disease as well as biochemical progression at 6 mos. was significantly lower in the SABR arm as compared to observation (19% vs. 61% and 11% and 50%, respectively). Moreover, median progression-free and as biochemical survival was prolonged with SABR, while local control was as high as 98.9% by the intervention. Notably, patients without additional untreated metastases detected by the PSMA-PET-CT outperformed their counterparts with by conventional imaging undetectable and thus untreated lesions in terms of a lower risk of progression at 6 mos. and expanded progression-free survival. Importantly, less of them also experienced new metastatic lesions at 180 days providing a longer distant metastasis-free survival. No grade 3 toxicities have been reported. High-risk mutation signature was identified as a predictive factor for the lack of the benefit from SABR.

The results of this trial are hypothesis-generating supporting further prospective research with long-term results. While some patients with OMPC do seem to benefit from metastasis-directed therapy that might postpone initiation of ADT, it might indeed open a window for cure for selected cases when combined with further aggressive systemic strategies. The finding that patients with a completely eradicated visualized disease (by PSMA-PET-CT) have a higher chance to remain free of new metastasis for a longer period of time, points to the modified natural course of disease by SABR. Immunologic issues underlying this abscopal effect including T-cell receptor clonality and its potential predictive value for the intervention success merit further research. Despite the fact that mutation analysis in the trial is limited to leukocyte DNA without being matched to tumor cells thus allowing for misinterpretation of some somatic mutations as being tumor-related, future extensive efforts on validation and expansion of these promising results aiding in marker-driven treatment decision are warranted.