Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS).

BACKGROUND: Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa. METHODS: Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. DISCUSSION: The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/- radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. TRIAL REGISTRATIONS: Clinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Online Prostate-Specific Membrane Antigen and Positron Emission Tomography-Guided Radiation Therapy for Oligometastatic Prostate Cancer.

PURPOSE: Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR). METHODS AND MATERIALS: A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (Dmax), mean dose to proximal organs at risk (DOAR), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects. RESULTS: RSABR and BgRT plans resulted in mean ± standard deviation increases in Dmax of 4 ± 11% (P = .21) and 18 ± 15% (P < .001) and reductions in DOAR of -20 ± 19% (P <.001) and -10 ± 19% (P = .02) compared with CSABR. Similar target coverage was maintained with conformity indices of 0.81 ± 0.04 (P < .001) and 0.72 ± 0.08 (P = .44) for RSABR and BgRT compared with 0.74 ± 0.08 for CSABR. Dose and log (specific uptake values) had Pearson correlation coefficients of 0.10 (CSABR), 0.16 (RSABR), and 0.31 (BgRT). CONCLUSIONS: BgRT plans provided similar PTV coverage and conformity compared with CSABR while incorporating underlying PET activity. These results demonstrate feasibility of BgRT optimization enabling online PSMA-targeted, PET-based tracked dose delivery for OMPC.

Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial.

Importance: Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT). Objective: 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. Interventions: 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. Results: 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). Conclusions and Relevance: Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Trial Registration: ClinicalTrials.gov Identifier: NCT02680587.

Stereotactic ablative radiation therapy for oligometastatic prostate cancer delays time-to-next systemic treatment.

PURPOSE: Local ablative treatment to oligometastatic patients can result in long-term disease-free survival in some cancer patients. The importance of this treatment paradigm in prostate cancer is a rapidly evolving field. Herein, we report on the safety and preliminary clinical outcomes of a modern cohort of oligometastatic prostate cancer (OPC) patients treated with consolidative stereotactic ablative radiation (SABR). METHODS: Records of men with OPC who underwent consolidative SABR at our institution were reviewed. SABR was delivered in 1-5 fractions of 5-18 Gray. Kaplan-Meier estimates of local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir + 2), distant progression-free survival (DPFS), and time-to-next intervention (TTNI) were calculated. RESULTS: In total, 66 OPC patients were identified with consolidative SABR delivered to 134 metastases: 89 bone, 40 nodal, and 5 viscera. The majority of men (49/66) had hormone-sensitive prostate cancer (HSPC). Crude grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no ≥ grade 3 toxicity. At 1 year, LPFS was 92% and bPFS and DPFS were 69%. Of the 18 men with HSPC who had deferred hormone therapy , 11 (56%) remain disease free following SABR (1-year ADT-FS was 78%). In 17 castration-resistant men, 11 had > 50% prostate-specific antigen (PSA) declines with 1-year TTNI of 30%. CONCLUSIONS: Consolidative SABR in OPC is feasible and well tolerated. The heterogeneity and small size of our series limit extrapolation of clinically meaningful outcomes following consolidative SABR in OPC, but our preliminary data suggest that this approach warrants continued prospective study.

Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy.

OBJECTIVES: Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS: We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS: Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION: PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.

Detectable end of radiation prostate specific antigen assists in identifying men with unfavorable intermediate-risk prostate cancer at high risk of distant recurrence and cancer-specific mortality.

BACKGROUND: Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. METHODS: A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. RESULTS: The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS (P = 0.008 and P = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS (P = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR-PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS (P = 0.021) and PCSS (P = 0.033), while RT dose also predicted PCSS (P = 0.013). CONCLUSIONS: EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men.

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

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 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/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. DISCUSSION: The 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 REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.