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238 Background: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state along the progression of metastatic disease in which patients experience improved outcomes compared to those with higher disease burden. Despite the generally more indolent nature, much heterogeneity still exists with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Here we correlate tumor genomics with modes of progression (MOP) and patterns of failure (POF) following treatment for omCSPC. Methods: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC, who underwent tumor next generation sequencing (NGS) with at least 1 year of follow-up. Descriptive POF and MOP were reported with respect to presence of genomic alterations in pathways of interest. Genomic pathways of interest included TP53, SPOP, WNT ( APC, CTNNB1, RNF43), DNA double strand break repair, cell cycle genes ( Rb1, CCND1–3, CDKN1B, and CDKN2A), and PI3K/AKT/mTOR. MOP were defined as oligoprogression (1-3 lesions), polyprogression (≥4 lesions), or long-term control (LTC, no radiographic progression at last follow-up). POF included location of lesions at first failure. Overall survival (OS) was calculated by the Kaplan-Meier method. Genomic associations with patterns/modes of failure were compared with chi-square test. Results: 221 patients were included for analysis with the majority having either 1 (47.5%) or 2 (27.3%) metastatic lesions at oligometastasis. 5-yr OS was associated with MOP 92% vs 89% vs 69% (p

5025 Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.

Purpose Retrospective studies suggest that metastasis-directed therapy (MDT) for oligorecurrent prostate cancer (PCa) improves progression-free survival. We aimed to assess the benefit of MDT in a randomized phase II trial. Patients and Methods In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography–computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy). Surveillance was performed with prostate-specific antigen (PSA) follow-up every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (≤ 3 v > 3 months) and nodal versus non-nodal metastases. The primary end point was androgen deprivation therapy (ADT)–free survival. ADT was started at symptomatic progression, progression to more than three metastases, or local progression of known metastases. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11). Quality of life was similar between arms at baseline and remained comparable at 3-month and 1-year follow-up. Six patients developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.

10 Background: Multiple randomized phase II trials suggest that metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa) improves progression-free survival, but the majority of trials lack longer follow-up. We present the updated 5-year results from the STOMP-trial. Methods: In this multicentre, randomised, phase II study, asymptomatic PCa patients were eligible in case of a biochemical recurrence following primary PCa treatment with curative intent and presenting with up to 3 extracranial on choline PET-CT and a serum testosterone levels > 50 ng/ml. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions. Randomisation was balanced dynamically on two factors: PSA doubling time (≤3 vs. > 3 months) and nodal vs non-nodal metastases. The primary endpoint was androgen deprivation therapy (ADT)-free survival. Castrate resistant prostate cancer-free survival (CRPC) was a secondary endpoint. Tests were performed two-sided; p values less than 0.20 were deemed significant. Results: The 5-year ADT-free survival was 8% for the surveillance group and 34% for the MDT group (Figure 1, hazard ratio 0.57 [80% CI: 0.38-0.84], log-rank p = 0.06). There was no significant difference in effect for the different stratification factors (interaction test). The 5-year CRPC-free survival was 53% for the surveillance group and 76% for the MDT group (hazard ratio 0.62 [80% CI: 0.35−1.09]; log−rank p = 0.27). At a median follow for survival of 5.3 years (IQR 4.3-6.3), the 5-year overall survival was 85%, with 6 out of 14 deaths attributed to prostate cancer. Conclusions: The updated STOMP trial outcomes confirm the earlier reported significant difference in ADT free survival in favor of the MDT group compared to surveillance. Prostate-cancer related mortality is low within the first 5 years of diagnosis of oligorecurrent prostate cancer. Clinical trial information: NCT01558427.

422 Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). The trial was approved by the Ethical Committee of Ghent University Hospital and is registered on ClinicalTrials.gov (NCT02826564). Funding was provided by Merck Sharp & Dohme. Results: Eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4-5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Conclusions: Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution and suggests a shared driver gene status throughout disease progression. Clinical trial information: NCT02826564.

TPS156 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.

153 Background: To identify sites and patterns of prostate cancer (PCa) recurrence following primary PCa treatment with 18F-choline PET/CT and estimate the number of patients potentially eligible for metastasis-directed therapy (MDT, defined as patients with up to 3 metastatic lesions). Methods: Between 7/7/2011 and 7/6/2016, 229 patients underwent a 18F-choline PET/CT for a biochemical PCa recurrence for potential inclusion in a randomized phase II-trial (STOMP). The trial randomizes patients with oligorecurrent (Orec) PCa between active surveillance (AS) and MDT. Patients were eligible for the trial in case of biochemical recurrence following primary prostate cancer treatment, up to 3 extracranial metastases and testosterone > 50 ng/ml. Patterns of recurrence were classified as local (prostate or prostate bed), distant (N1, M1a/b/c) or a combination of both. The number of lesions were counted per scan and patients with up to 3 distant lesions with or without a local recurrence were considered as ORec vs > 3 lesions as polyrecurrent (PRec). Results: A total number of 229 patients underwent 277 choline PET-CTs, resulting in 208 patients (91%) with a recurrence and 21 patients (9%) without any detectable recurrence. Twenty-two men (10%) had a local recurrence and 186 men (81%) had a distant recurrence, which was combined with a local recurrence in 17 men. Of the 186 patients, 131 (57%) were considered as ORec and 55 (24%) as PRec at median PSA values of 3.4 and 5.4 ng/ml, respectively (p < 0.003). ORec were categorized as N1: 16%, M1a: 8%, M1b: 13%, M1c: 2% or a combination of sites: 17% (Figure 1). Fifty-eight patients had 1 lesion (25%), 39 2 lesions (17%) and 34 3 lesions (15%). Men with ORec PCa were treated with AS, MDT or palliative ADT in respectively 27%, 27% and 1% of the cases. Sixty-two of ORec men (27%) agreed to be randomized in the STOMP-trial. PRec were categorized as N1: 2%, M1a: 1%, M1b: 3%, M1c: 1% or a combination: 17% (Figure 1). Thirteen patients had 4 lesion (6%), 9 5 lesions (4%) and 33 > 5 lesions (18%) Conclusions: Two out of three PCa recurrences on 18F-choline PET-CT are potentially salvageable with local therapy and/or metastasis-directed therapy. Clinical trial information: NCT01558427.

69 Background: Approximately 25% of patients treated with immediate post-prostatectomy (adjuvant) radiotherapy will develop a biochemical failure within 5 years after radiotherapy when doses of 60-64 Gy are used. We wanted to report on the safety and biochemical outcome of adjuvant intensity-modulated radiotherapy (AIMRT) with a median dose of 74 Gy. Methods: Between 1999 and 2008, 104 patients underwent a radical prostatectomy followed by AIMRT +/− androgen deprivation (AD). Indications for AIMRT were capsule perforation, seminal vesicle invasion and/or positive surgical margins at prostatectomy specimen. All patients were irradiated at a single tertiary academic centre. AD was initiated in 65% of the patients on the basis of seminal vesicles invasion, pre-prostatectomy PSA > 20ng/mL, Gleason score ≥ 4+3 or personal preference of the referring urologist. A median dose of 74 Gy was prescribed to the planning target volume using IMRT in all patients. AD consisted out of a LHRH analogue for 6 months. The Kaplan-Meier method was used to estimate biochemical relapse-free survival (bRFS). Univariate and multivariate analysis were used to examine the influence of patient- and treatment-related factors on bRFS. Results: The median follow-up was 5 years. Late toxicity: no patients developed grade 3 gastrointestinal (GI) toxicity. Grade 2 GI toxicity was seen in 8%. Seven patients (7%) and 24 (23%) developed grade 3 and 2 genitourinary (GU) toxicity, respectively. An urethral stricture was observed in 8 patients (8%). The 3- and 5-year actuarial bRFS was 91% and 85%, respectively. On univariate analysis bRFS rates was reduced with seminal vesicle invasion (p < 0.04) or Gleason score ≥ 4+3 (p < 0.02) or negative margins (p < 0.001). AD and preoperative PSA levels did not influence bRFS. None of the variables remained significant on multivariate analysis.Eight patients had a distant clinical relapse (pelvic lymph nodes: 3, bone metastases: 3 and 2 patients had both). Seven patients died (3 prostate cancer related deaths). Conclusions: Adjuvant high-dose IMRT after prostatectomy is safe. Five-year bRFS is excellent. No significant financial relationships to disclose.