ESTRO 2023 - Abstract Book

S331

Sunday 14 May 2023

ESTRO 2023

Purpose or Objective Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in men and remains a significant health burden worldwide. Ionising radiation (IR) is the standard-of-care treatment for locally advanced PCa, however 20-50% of men relapse to more advanced disease. Aberrant epigenetic dysregulation of cancer DNA modulates gene expression and plays a key role in the development and progression of PCa. In particular, the imbalance of acetylation through overexpression of histone deacetylases (HDACs) can epigenetically silence genes through deacetylation. Such HDAC mediated gene silencing plays a key role in the development of resistance, therefore HDAC inhibition is an attractive therapeutic approach. We hypothed Class I HDAC inhibitor Entinostat (Ent) would induce anti-tumour effects and synergise with IR in prostate tumours. Materials and Methods Prostate cancer cell lines were treated with IR or Ent alone and in combination. Differentially expressed genes and enriched gene sets were analysed following RNA sequencing. PCa cell survival and levels of apoptosis were assessed via colony- forming assays and flow cytometry. The synergistic effects of Ent and IR were further investigated in vivo - human PCa cells were implanted in mouse xenograft models, with formed tumours subsequently treated with Ent, IR or Ent in combination with IR. Results RNA sequencing revealed Ent targets pathways including DNA damage and cell cycle in PCa cells, with DNA repair regulators BRCA1 and RAD51 significantly downregulated in response to Ent. Ent increased the sensitivity of PCa cells to radiation in vitro, with combined Ent and IR reducing clonogenic survival and significantly increasing apoptosis versus single agent controls after 24h treatment. Ent synergised with radiotherapy in vivo, with combination treatment causing the most significant reduction in tumour growth versus vehicle controls. Both single agent and combination therapies were well tolerated in mouse models. Gene Set Enrichment Analysis (GSEA) revealed a role for p53 signalling enrichment and mTOR signalling suppression in the radiosensitisation effect on Ent in PCa cells. Conclusion Analysis of transcriptomic data identified DNA repair as being significantly repressed in response to Class I HDAC inhibition, suggesting potential for therapeutic combination with DNA-damaging IR. Ent resulted in a synergistic response to DNA damage induced by radiotherapy in vitro and in vivo, demonstrating potential to be integrated as a novel treatment strategy for PCa. OC-0431 Randomised phase II trial of adaptive image guided bladder radiotherapy: patient reported outcomes R. Huddart 1,2 , A. Birtle 3 , K.C. Cheung 4 , A. Choudhury 5 , F. Foroudi 6 , H. Gribble 4 , C. Griffin 4 , S. Hafeez 1,7 , E. Hall 4 , A. Henry 8 , B. Hindson 9 , R. Lewis 4 , D. McLaren 10 , H. McNair 1,7 , A. Nikapota 11 , A. Omar 4 , O. Parikh 12 , L. Philipps 4 , I. Syndikus 13 , M. Varughese 14 , C. Vassallo-Bonner 15 , A. Webster 16 1 The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom; 2 Royal Marsden Hospital NHS Foundation Trust, Radiotherapy Department, London, United Kingdom; 3 Lancashire Teaching Hospitals NHS Foundation Trust, Cancer Oncology, Preston, United Kingdom; 4 The Institute of Cancer Research, Clinical Trial and Statistics Unit, London, United Kingdom; 5 The Christie NHS Foundation Trust, Translational Radiobiology, Manchester, United Kingdom; 6 Austin Health, Radiation Oncology, Austin, Australia; 7 The Royal Marsden NHS Foundation Trust, Radiotherapy Department, London, United Kingdom; 8 Leeds Teaching Hospitals NHS Trust, Division of Cancer Studies and Pathology, Leeds, United Kingdom; 9 Canterbury District Health Board, Department of Oncology Services, Christchurch, New Zealand; 10 NHS Lothian, Department of Oncology, Edinburgh, United Kingdom; 11 Brighton and Sussex University Hospital NHS Trust, Clinical Oncology, Brighton, United Kingdom; 12 Lancashire Teaching Hospitals NHS Trust, Oncology, Burnley, United Kingdom; 13 The Clatterbridge Cancer Centre, Department of Radiotherapy, Liverpool, United Kingdom; 14 Royal Devon & Exeter NHS Foundation Trust, Department of Oncology, Exeter, United Kingdom; 15 The Institute of Cancer Research, Patient representative, London, United Kingdom; 16 University College Hospital (UCLH), National Radiotherapy Trials Quality Assurance Group (RTTQA), London, United Kingdom Purpose or Objective Radiotherapy (RT) to the bladder is challenging as it is a mobile, deformable structure. Plan of the day (POD) adaptive image-guided RT and tumour boost dose escalation can optimise treatment. We aimed to define a feasible, safe schedule for muscle-invasive bladder cancer (BC) using these techniques. Materials and Methods RAIDER (ISRCTN 26779187) is an international phase II trial. Participants (pts) had unifocal T2-T4a urothelial BC and were randomised (1:1:2) to standard whole bladder RT (WBRT), standard dose adaptive tumour focused RT (SART) or dose- escalated adaptive tumour boost RT (DART). Two fractionation (f) schedules recruited independently. WBRT & SART dose was 64Gy/32f or 55Gy/20f and DART was 70Gy/32f or 60Gy/20f. For SART & DART, POD (small, medium, large) was chosen daily. Patient-reported outcomes (PRO) included the King’s Health Questionnaire (KHQ) and EQ5D-5L as key secondary endpoints and PRO-CTCAE collected before, during and after RT. Standard algorithms were used to derive scores: EQ5D general health score, KHQ bladder problem score, KHQ symptom severity scale In each fractionation cohort, data are presented by treatment received in pts who received at least 1f RT. Results 345 pts were randomised: 46/41 WBRT, 46/41 SART and 90/81 DART pts in 32f/20f cohorts respectively. 170 (93%) 32f and 149(91%) 20f pts consented to the PRO substudy and started RT. Baseline characteristics for 32f/20f were median age 73 years (IQR 68-79)/72 (67-79); 84%/77% T2; 46%/56% had NAC and 71%/70% concomitant radiosensitising treatment. Median follow-up was 32f: 38 months (m) (IQR 26-50), 20f: 42m (36-50). For 98% of SART/DART pts >1 RT plan was used with 3588/6222 (58%) fractions using adaptation (small or large plan). PRO reported at last RT fraction and at 12m are shown (table) with KHQ bladder problem ratings and PRO-CTCAE stool frequency at 12m (figure). Proffered Papers: Genito-urinary