A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE)

Noura Radwan,Ryan Phillips,Daniel Y Song,Steven P Rowe,Mario A Eisenberger ,Channing J Paller ,Michael A Carducci ,Adam P Dicker ,Theodore L Deweese,Ashley E Ross ,Martin G Pomper,Kenneth J Pienta,Hao Wang,Curtiland Deville,Maximilian Diehn,Emmanuel S Antonarakis,Michael A Gorin,Stephen Greco,Samuel R Denmeade ,Phuoc T Tran

doi:10.1186/s12885-017-3455-6

Abstract

BackgroundWe describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F–DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease.Methods/designPatients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher’s exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory.DiscussionThe ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state.Trial registrationsClinicalTrials.gov Identifier: NCT02680587.URL of Registry: https://clinicaltrials.gov/show/NCT02680587Date of Registration: 02/08/2016.Date of First Participant Enrollment: 05/23/2016.

Highlights

We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued
In the modern era with conventional imaging, oligometastatic hormone sensitive prostate cancer likely comprises a large number of men, possibly the majority of men following failed primary therapy [25,26,27,28]. Assuming these men are at a potentially curable state before castration-resistance develops, we need additional treatment strategies to re-examine this large cohort of men. Based on this emerging evidence, we propose a phase II study of SABR in patients with oligometastatic hormone sensitive prostate cancer
Complete Response (CR): Disappearance of all target lesions and Prostate specific antigen (PSA) below baseline Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum OR at least 1/3 of lesions are stable or resolved by bone scan AND PSA below baseline Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment initiation OR the appearance of >1 new lesion(s) by bone scan OR PSA ≥25% above nadir or > 50 ng/ml

Summary

Introduction

Non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. The presence of an oligometastatic state, at which point metastases are limited in number and location, was originally proposed by Hellman and Weichselbaum, who suggested that these patients would benefit from effective local therapy in addition to systemic therapy [1]. The treatment of metastases depends on multiple factors including 1) the location of the primary tumor, 2) the size, number and location of metastases, 3) the availability and effectiveness of therapies (e.g. surgery, radiation, and chemotherapy), and 4) the patient’s functional status. Highly accurate radiation at tumorocidal doses can be delivered in 1 to 5 outpatient treatments [4,5,6,7,8]

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