Stereotactic Body Radiation for Prostate Oligometastases (ORIOLE)

Phase II Randomized Observation Versus Stereotactic Ablative RadiatIOn for OLigometastatic Prostate CancEr (ORIOLE) Trial

Men with oligometastatic prostate cancer lesions will be randomized (1:2) to observation versus SBRT. The study will NOT be blinded. Within three weeks of the initial treatment planning, SBRT (1-5 fractions) will be administered.

This research is being done to determine if we can improve the outcome of prostate cancer patients who have failed primary treatment - surgery or local radiation to the prostate - and have 3 or fewer bone metastases. Patients with metastatic prostate cancer disease will usually be placed on hormonal therapy which can work well for a period of time, but hormonal therapy can have side effects that greatly trouble men. Any effort to delay the start of hormonal therapy would be an advantage to the patient. Radiation treatment usually takes many weeks to deliver and is not given in a high enough doses to metastases to prevent them from coming back locally. Stereotactic body radiation therapy (SBRT) is highly focused radiation, given in a very dose intensive fashion and delivered in usually less than one week. Stereotactic body radiation has been shown to be very effective on bone metastases. Therefore, we are studying the effects of stereotactic body radiation treatment on patients with five or fewer prostate cancer bone metastases to determine if we can stall the use of hormonal therapy and/or prevent other bone metastases from developing elsewhere in the body. Additionally, fundamental analysis of the oligometastatic state with be achieved through correlation with investigational DCFPyL-positron emission tomography (PET) imaging, which can help us find cancer that has spread (metastatic disease) from its original site in people who have cancer in their prostate to other parts of their body. Specifically, 54 men with biochemically recurrent, oligometastatic prostate adenocarcinoma will be accrued across 3 centers in the United States. Patients were stratified by primary intervention (surgery vs radiotherapy), prior hormonal therapy, and PSA doubling time, then randomized 2:1 to SBRT or observation. The primary clinical endpoint is progression at 6 months from randomization with the hypothesis that SBRT to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints include local control at 6 months post-SBRT, SBRT-associated toxicity and quality of life, and ADT-free survival (ADT-FS). Alterations in the biology of the oligometastatic state induced by stereotactic ablative radiotherapy (SABR) will be investigated using leading-edge correlatives, including: analysis of circulating tumor cells (CTCs; Epic Sciences, San Diego, CA), deep sequencing of circulating tumor DNA (ctDNA) using Cancer Personalized Profiling by deep sequencing (CAPP-Seq) to non-invasively assess tumor burden, and ImmunoSEQ profiling of T-cell repertoires to elucidate the immunological response to SABR (Adaptive Technologies, Seattle, WA). Lastly, the use of the Color Genomics platform (Burlingame, CA), a hereditary cancer assay assessing pathogenic mutations in 30 cancer predisposition genes that account for >90% of the germline mutations known to occur in men with castrate resistant metastatic prostate cancer (mCRPC), will help inform and allow for efforts to advance a more personalized medicine approach to tailor screening and therapies in these men.

Prostate Cancer, Stereotactic Body Radiation Therapy, Stereotactic Ablative Radiotherapy, Oligometastasis

Men with oligometastatic prostate cancer lesions randomized to stereotactic body radiation therapy (SBRT).

Number of participants who progressed at 6 months. Progression is defined as either: 1) a ≥ 25% increase in PSA from nadir (and by ≥ 2 ng/mL), requiring confirmation ≥ 4 weeks later (PCWG2 criteria); and/or, 2) clinical/radiographic-progression defined as symptomatic progression (worsening disease-related symptoms or new cancer-related complications), or radiologic progression (on CT scan: ≥ 20% enlargement in sum diameter of soft-tissue target lesions [RECIST1.1 criteria]; on bone scan: ≥ 1 new bone lesions),initiation of ADT or death due to any cause, whichever occurs first.

Number of lesions that did not increase in size by at least 20% or more on CT from baseline to 6 months.

We will assess quality of life following completion of Stereotactic Body Radiation Therapy via Brief Pain Inventory questionnaire made up of 9 questions. Each question scores from 0-10, with higher scores mean worse outcome or more pain. An overall score, calculated by adding the scores for questions 2, 3, 4 and 5 and then dividing by 4, will be calculated pre-treatment and at the time of day 180. The change in score (between baseline and 6 months) will be evaluated.

18F-DCFPyL Positron Emission Tomography (PET)/MRI or -PET/CT positive sites that are positive for new or progressive metastatic disease by bone scan/CT at 6-months following SBRT.

Androgen Deprivation Therapy-free survival will be assessed using the number of participants deceased at 6 months.

Inclusion Criteria: Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone or soft tissue develop within the past 6-months that are ≤ 5.0 cm or <250 cm3. Patient must have had their primary tumor treated with surgery and/or radiation. Histologic confirmation of malignancy (primary or metastatic tumor). PSADT <15 months. PSA doubling time (PSADT) will be calculated using as many PSA values that are available from time of relapse (PSA > 0.2). To calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate Cancer Prediction Tool will be used. It can be found at the following web site: https://www.mskcc.org/nomograms/prostate/psa-doubling-time. Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy (to the primary prostate cancer or pelvis is allowed). PSA >1 but <50. Testosterone > 125 ng/dL. Patient must have a life expectancy ≥ 12 months. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Patient must have normal organ and marrow function as defined as: Leukocytes >2,000/μL Absolute Neutrophil Count >1,000/μL Platelets >50,000/μL - Patient must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment. DCFPyL-PET/MRI or DCFPyL-PET/CT scan within the past 6 months with results that demonstrate more disease lesions than baseline CT/Bone Scan Castration-resistant prostate cancer (CRPC). Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis). Patient receiving any other investigational agents. Patient is participating in a concurrent treatment protocol. Total bilirubin > 3 times the upper limit of normal. Liver Transaminases > 5-times the upper limit of normal. Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT. Liver Transaminases > 5-times the upper limit of normal. Prior salvage treatment to the primary prostate cancer or pelvis is allowed. Refusal to sign informed consent.

Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, Rowe SP, Ross AE, Gorin MA, Deville C, Greco SC, Wang H, Denmeade SR, Paller CJ, Dipasquale S, DeWeese TL, Song DY, Wang H, Carducci MA, Pienta KJ, Pomper MG, Dicker AP, Eisenberger MA, Alizadeh AA, Diehn M, Tran PT. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):650-659. doi: 10.1001/jamaoncol.2020.0147.

Radwan N, Phillips R, Ross A, Rowe SP, Gorin MA, Antonarakis ES, Deville C, Greco S, Denmeade S, Paller C, Song DY, Diehn M, Wang H, Carducci M, Pienta KJ, Pomper MG, DeWeese TL, Dicker A, Eisenberger M, Tran PT. A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). BMC Cancer. 2017 Jun 29;17(1):453. doi: 10.1186/s12885-017-3455-6.

Deek MP, Van der Eecken K, Sutera P, Deek RA, Fonteyne V, Mendes AA, Decaestecker K, Kiess AP, Lumen N, Phillips R, De Bruycker A, Mishra M, Rana Z, Molitoris J, Lambert B, Delrue L, Wang H, Lowe K, Verbeke S, Van Dorpe J, Bultijnck R, Villeirs G, De Man K, Ameye F, Song DY, DeWeese T, Paller CJ, Feng FY, Wyatt A, Pienta KJ, Diehn M, Bentzen SM, Joniau S, Vanhaverbeke F, De Meerleer G, Antonarakis ES, Lotan TL, Berlin A, Siva S, Ost P, Tran PT. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J Clin Oncol. 2022 Oct 10;40(29):3377-3382. doi: 10.1200/JCO.22.00644. Epub 2022 Aug 24.