Noura Radwan

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.

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.

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. 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. 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. 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.

5020 Background: The importance of local treatment in oligometastatic prostate cancer (OPC) is unknown. Stereotactic ablative radiotherapy (SABR) is highly focused, high-dose radiation that is well suited for treatment of oligometastases. Here we report on the safety and preliminary clinical outcomes of SABR in a modern cohort of OPC men. Methods: Eighty four men who satisfied criteria of OPC diagnosed on imaging underwent consolidative SABR were then followed prospectively on our IRB approved registry by our GU multidisciplinary team. We collected demographic, clinical, toxicity and efficacy information. We examined the first 66 men in this preliminary report to allow for a minimum of 4.5 months follow-up. SABR was delivered in 1-5 fractions of 5-18 Gy. Kaplan-Meier method was used to assess local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir+2), distant progression free survival (DPFS), ADT-free survival (ADT-FS) and time-to-next intervention (TTNI). Results: Of the 66 OPC patients analyzed, 25 (38%) men presented as synchronous OPC and the remaining 41 had recurrent OPC. Median and mean follow-up was 61 and 66 weeks, respectively. Patient and disease factors as listed in the Table. Crude Grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no Grade > 2 toxicity. SABR was delivered to 134 metastases: 89 bone (66%), 40 nodal (30%) and 5 (4%) visceral metastases. Overall LPFS at 1-year was 92%. The bPFS and DPFS at 1-year were 69% and 69%, respectively. Median TTNI was not reached yet. Of the 18 men with hormone sensitive prostate cancer who had their ADT deferred, 11/18 (56%) remain free of disease following SABR (1-year ADT-FS was 78%) and in 17 castration resistant men, 11 had > 50% PSA declines with 1-year TTNI of 30% with a median of 45 weeks. Conclusions: Consolidative SABRfor OPCis feasible and well tolerated. The preliminary clinical outcomes in our series is limited by heterogeneity and size but our data suggests that this approach is worthy of further prospective study. [Table: see text]

TPS5094 Background: ORIOLE is a randomized, non-blinded Phase II interventional study evaluating the safety and efficacy of SBRT in biochemically recurrent, oligometastatic, hormone-sensitive prostate cancer at 3 centers in the US. Patients will be stratified by clinical characteristics and randomized 2:1 to SBRT or observation. The primary clinical endpoint is progression at 6 months defined by PSA increase, radiologic or clinical evidence, ADT initiation, or death from any cause. Secondary endpoints include local control at 6 months, SBRT-associated toxicity and quality of life, and ADT-free survival. Imaging and laboratory correlates will characterize, in isolation, the effects of SBRT on oligometastatic disease. Methods: Eligible patients are hormone-sensitive, have undergone prior definitive treatment and recurred with 1-3 asymptomatic bone or soft tissue metastases diagnosed within 6 months, PSA doubling time (PSADT) < 15 months, ECOG performance status ≤ 2, and normal organ and marrow function. Minimization will be used to balance assignment by primary intervention, prior ADT, and PSADT. Accrual of 54 patients provides 85% power to detect a decrease in progression rate from 80% to 40% with type I error = 0.05 using one-sided Fisher’s exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival, ADT free survival, and time to locoregional and distant progression will be calculated based on intention-to-treat. Local control will be assessed using RECIST 1.1 criteria. Withdrawal prior to 6 months will be counted as progression. Adverse events will be summarized and quality of life pre- and post-SBRT will be measured by Brief Pain Inventory. The investigational targeted imaging agent ¹⁸F-DCFPyL will be compared to bone scan and CT for identifying oligometastases before SBRT and monitoring disease response following SBRT. Biological alterations induced by SBRT will be investigated using circulating tumor cell analysis, deep sequencing of circulating tumor DNA, and T-cell repertoire profiling. A hereditary cancer assay will inform efforts to advance personalized screening and therapy. Clinical trial information: NCT02680587.

In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as 0.1 ng ml⁻¹) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan–Meier survival curves were constructed, with stratification by EOR PSA. At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, PP=0.003), 10-year PCSS (94.3% versus 98.2%, P=0.007) and 10-year OS (75.8% versus 82.5%, P=0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37–14.65, PP=0.168). Main study limitations are retrospective study design and associated biases. EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.

To evaluate the relationship between PSA testing history and high-risk disease among older men diagnosed with prostate cancer. Records from 1993 to 2014 were reviewed for men who underwent radiotherapy for prostate cancer at age 75 years or older. Patients were classified into one of four groups based on PSA-testing history: (1) no PSA testing; (2) incomplete/ineffective PSA testing; (3) PSA testing; or (4) cannot be determined. Outcomes of interest were National Comprehensive Cancer Network (NCCN) risk group (that is, low, intermediate or high risk) and biopsy grade at diagnosis. Multivariable logistic regression was used to determine the association between PSA testing history and high-risk cancer. PSA-testing history was available in 274 (94.5%) of 290 subjects meeting study criteria. In total, 148 men (54.0%) underwent PSA testing with follow-up biopsy, 72 (26.3%) underwent PSA testing without appropriate follow-up, and 54 men (19.7%) did not undergo PSA testing. Patients who underwent PSA testing were significantly less likely to be diagnosed with NCCN high-risk cancer (23.0% vs 51.6%, PP<0.001) as compared to the tested population. Older men who underwent no PSA testing or incomplete testing were significantly more likely to be diagnosed with high-risk prostate cancer than those who were previously screened. It is reasonable to consider screening in healthy older men likely to benefit from early detection and treatment.