A phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer (ORIOLE).

Abstract

Background: 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. 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 18 F-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/design: Patients 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.

Patterns of Recurrence and Modes of Progression After Metastasis-Directed Therapy in Oligometastatic Castration-Sensitive Prostate Cancer

“…[3][4][5] Within the oligometastatic prostate cancer literature, the Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence (STOMP) and Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) trials reported prolonged androgen deprivation therapy (ADT)efree survival and PFS after MDT compared with observation. 6,7 These findings are also supported by several retrospective studies showing sustained periods of PFS, ADT-free survival, and time to next intervention (TTNI) with MDT. [8][9][10][11][12][13][14][15] Collectively, these results have led to an increasing trend to treat oligometastatic lesions with MDT to improve OS and PFS, delay initiation of systemic therapies with unfavorable toxicity profiles, and offer treatment breaks for individuals amassing toxicity from systemic therapy.…”

Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

“…Currently, increasing data are showing that MDT for oHSPC improves PFS without significant side effects, in contrast to the toxicity related to ADT [8,9,11]. In this setting, 177 Lu-PSMA is anticipated to be effective coupled with low grade toxicity.…”

“…Particularly, patients with a limited number of metastases (≤5 metastases), so called 'oligometastatic' PC, seem to benefit from MDT. Here, EBRT offers an ADT free survival of 14 to 29 months with solely low-grade treatment related side effects [8][9][10][11][12]. Therefore, several clinical trials are currently investigating MDT in this hormone sensitive oligometastatic setting (clinicaltrials.gov: NCT03569241, NCT04075305, NCT02170181, NCT04302454, NCT02192788, NCT02685397, NCT04115007, NCT02264379, NCT02680587, NCT03630666, NCT02274779, NCT03795207, NCT03525288, NCT03784755).…”

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting

“…For example, in a recent study by Tran and colleagues, the use of 18 F-DCFPyL PET imaging to guide treatment with stereotactic ablative radiotherapy to sites of spread in the oligometastatic setting significantly improved distant metastasisfree survival times compared to conventional imaging. 23 PSMA PET is also being used for the selection and therapeutic monitoring of patients for PSMA-RNT (discussed extensively in following sections) and other PSMA-targeted approaches. Other roles of PSMA PET in patients with advanced/metastatic castration-resistant disease remain to be defined.…”