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Poster session 18

1772P - Characterisation of a DNA repair deficiency (DRD) biomarker phenotype in metastatic urothelial carcinoma (mUC) within the ATLANTIS clinical trial platform

Date

10 Sep 2022

Session

Poster session 18

Topics

Clinical Research;  Translational Research;  Targeted Therapy

Tumour Site

Urothelial Cancer

Presenters

Simon Crabb

Citation

Annals of Oncology (2022) 33 (suppl_7): S785-S807. 10.1016/annonc/annonc1080

Authors

S.J. Crabb1, L. Dempsey2, E. Soulis2, S. Hinsley2, Y.P. Song3, J. Barber4, J. Frew5, J. Gale6, G. Faust7, S. Brock8, U.B. McGovern9, O.A. Parikh10, D. Enting11, S. Sundar12, G. Ratnayake13, K. Lees14, S.A. Hussain15, T.B. Powles16, R.J. Jones2, W. Tapper17

Author affiliations

  • 1 Southampton Experimental Cancer Medicine Centre, University of Southampton, SO16 6YD - Southampton/GB
  • 2 Cruk Glasgow Clinical Trials Unit, University of Glasgow, G12 8QQ - Glasgow/GB
  • 3 Clinical Oncology Department, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 4 Clinical Oncology Department, Velindre Cancer Centre - Velindre NHS University Trust - NHS Wales, CF14 2TL - Cardiff/GB
  • 5 Clinical Oncology Department, The Freeman Hospital (NHS Foundation Trust) Northern Centre for Cancer Care, NE7 7DN - Newcastle-upon-Tyne/GB
  • 6 Medical Oncology Department, St. Mary's Hospital Portsmouth Oncology Centre, PO3 6AD - Portsmouth/GB
  • 7 Medical Oncology Department, Leicester Royal Infirmary - University Hospitals of Leicester NHS Trust, LE1 5WW - Leicester/GB
  • 8 Clinical Oncology Department, University Hospitals Dorset, Poole/GB
  • 9 Medical Oncology Department, UCLH - University College London Hospitals NHS Foundation Trust, NW1 2PG - London/GB
  • 10 Oncology, Royal Preston Hospital-Lancashire Teaching Hospitals NHS Foundation Trust, PR2 9HT - Preston/GB
  • 11 Department Of Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, SE1 9RT - London/GB
  • 12 Dept Of Oncology, Nottingham City Hospital, NG5 1PB - Nottingham/GB
  • 13 Medical Oncology, Musgrove Park Hospital - Taunton and Somerset NHS Foundation Trust, TA1 5DA - Taunton/GB
  • 14 Clinical Oncology Department, Musgrove Park Hospital - Taunton and Somerset NHS Foundation Trust, TA1 5DA - Taunton/GB
  • 15 Department Of Oncology And Metabolism, University of Sheffield, S10 2SJ - Sheffield/GB
  • 16 Oncology Department, St. Bartholomew's Hospital - Barts Health NHS Trust, EC1A 7BE - London/GB
  • 17 Human Development And Health, University of Southampton, SO17 1BJ - Southampton/GB

Resources

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Abstract 1772P

Background

A subset of mUC exhibits a DRD phenotype predicting benefit from platinum based chemotherapy (PBC). We previously reported switch maintenance therapy with the PARP inhibitor rucaparib, following PBC, in patients with mUC harbouring a DRD biomarker. Rucaparib extended progression free survival (Crabb et al, J Clin Oncol 40, 2022 (suppl 6; abstr 436)). We undertook an exploratory analysis of the phenotypic and genomic characteristics of the DRD biomarker allocated cohort, involving all patients from the ATLANTIS clinical trial where next generation sequencing (NGS) was possible.

Methods

DRD biomarker allocation was performed using the FoundationOne NGS assay of over 300 cancer related genes. Biomarker positive status was based on high (≥10%) percentage genome wide loss of heterozygosity (%LOH) and/or somatic alteration within defined DRD associated genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L) and/or germline mutations in BRCA1 or BRCA2. Somatic alterations were analysed using Maftools and survival outcomes by logrank testing.

Results

248 patients were screened for DRD biomarker status and biomarker allocation was possible in 194 (78%). 78/194 (40%) were biomarker positive with 20/78 (26%) due to a gene alteration, 47/78 (60%) by high %LOH and 11/78 (14%) both. Median overall survival from commencing PBC in biomarker defined patients was 95.6 weeks (95% CI 71.0-127) in biomarker positive versus 70.1 weeks (95% CI 52.4-102) in biomarker negative patients (p=0.07). Mean tumour mutational burden was greater in DRD biomarker positive patients (p=0.003). KAT6A (odds ratio (OR) 7.3, p=0.008), TERC (OR Inf, p=0.010, AKT2 (OR 9.4, p=0.02) and FGFR3 (OR 0.43, p=0.04) were differentially altered with respect to biomarker positive versus negative groups, although none retained significance after false discovery rate correction (n=43 genes mutated in at least 5 samples).

Conclusions

DRD biomarker positive mUC was associated with higher tumour mutational burden. Trends were also found for extended overall survival following PBC and differential somatic gene alteration status.

Clinical trial identification

ISRCTN25859465.

Editorial acknowledgement

Legal entity responsible for the study

NHS Greater Glasgow & Clyde and the University of Glasgow.

Funding

Cancer Research UK; Clovis Oncology.

Disclosure

S.J. Crabb: Financial Interests, Personal, Advisory Board: Roche, MSD, AstraZeneca, Astellas, Novartis, EMD, Bayer, Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca, Astellas, Bayer, Janssen; Financial Interests, Personal, Expert Testimony: Pfizer/Merck, MSD; Financial Interests, Institutional, Funding: AstraZeneca, Astex Pharmaceuticals, Clovis Oncology, Roche; Financial Interests, Personal, Funding: AstraZeneca. D. Enting: Financial Interests, Institutional, Invited Speaker, Janssen Prostate Cancer UK Summit: Janssen; Financial Interests, Institutional, Advisory Board, Ra223 ad board: Bayer; Financial Interests, Institutional, Other, Bladder Cancer Preceptorship: Astellas. S. Sundar: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Bayer. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers-Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd.; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers-Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai. R. Jones: Financial Interests, Personal, Advisory Board, advisory board attendance: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker, Honoraria for speaking: Astellas; Financial Interests, Personal, Advisory Board: Bayer, Clovis, Exelixis, Ipsen, Bristol Myers Squipp, Merck Serono, Merck Sharpe Dome, Roche, Janssen, Novartis / AAA; Financial Interests, Personal, Invited Speaker: Bayer, Ipsen, Bristol Myers Squibb, Merck Serono, Merck Sharpe Dome, Pfizer, Roche, Janssen; Financial Interests, Institutional, Other, IDMC membership: Roche; Financial Interests, Institutional, Other, IDMC member: Stab; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Tail, AstraZeneca, BioXcel, Bristol Myers Squibb, Novartis / AAA, Roche, MSK. All other authors have declared no conflicts of interest.

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