Title: TRANS CeNtuRIOn
Funder: Cancer Research UK

Abstract: Background: 90% patients with ovarian cancer become resistant to platinum therapies and 5 year survival remains poor at ~36%. The median progression-free survival (PFS) for relapsed ovarian cancer (ROC) patients in CeNtuRIOn is 4- 9 months with overall survival (OS) of ~12-20 months. There is an urgent need to improve outcomes for patients with ROC of whom approximately 50% harbour homologous recombination repair deficiencies (HRD). HRD has been successfully exploited using PARP inhibitors (PARPi) in ROC patients with germline BRCA1/2 mutations. Many more patients with ROC are BRCA wildtype (wt) yet PARPi also show worthwhile activity in some. Programmed Death Receptor 1 (PD-1) and Cytotoxic T-lymphocyte Antigen 4 (CTLA4) have known roles in the suppression of T-cell responses and their over-expression in ovarian cancer is associated with a poorer prognosis. Increased heterogeneity in cancers correlates with improved efficacy of checkpoint inhibitors, thought to be related to the prevalence of tumour specific or neoantigens acting as neodeterminants. HRD related ovarian cancers harbour more neoantigens and have increased tumour infiltrating lymphocytes. CeNtuRIOn is a multi-centre randomised study for patients with HRD ROC (PARPi alone versus or combinations of PARPi with antiPD-1 monoclonal antibody alone or also with additional antiCTLA4 monoclonal antibody. Aim: To collect archival / diagnostic, pre-treatment and post-treatment tissue from as many recruited patients as possible. To collect circulating tumour cells, plasma for ctDNA and serum for cytokine analysis from all recruited patients before, during and after study therapy. Methods: Archival diagnostic FFPE tissue will be collected for Next Generation Sequencing, pre-and post-treatment biopsies will also be sought from any patient that has recurrent ovarian cancer metastases accessible to image guided biopsy. Whole blood will be taken at various time-points before, during and after study therapy. This will be used to extract DNA from circulating tumour cells, isolate plasma for storage of ctDNA and extract serum for future cytokine analysis. How the results of the research will be used: The collected samples will be used to explore any changes in tissue and blood during PARPi +/- immunotherapy. Signatures in tissue / blood will be sought that might identify patients who will respond to such therapies in the future. Larger phase III trials will be used to confirm / refute these proposed hypotheses. Data from this sample collection will also allow sensible estimates of the types and numbers of patients required to show statistical significance for these hypotheses at Phase III.

Lay abstract: Background: 90% patients with ovarian cancer become resistant to platinum therapies and 5 year survival remains poor at ~36%. The median progression-free survival (PFS) for relapsed ovarian cancer (ROC) patients in CeNtuRIOn is 4- 9 months with overall survival (OS) of ~12-20 months. There is an urgent need to improve outcomes for patients with ROC of whom approximately 50% harbour homologous recombination repair deficiencies (HRD). HRD has been successfully exploited using PARP inhibitors (PARPi) in ROC patients with germline BRCA1/2 mutations. Many more patients with ROC are BRCA wildtype (wt) yet PARPi also show worthwhile activity in some. Programmed Death Receptor 1 (PD-1) and Cytotoxic T-lymphocyte Antigen 4 (CTLA4) have known roles in the suppression of T-cell responses and their over-expression in ovarian cancer is associated with a poorer prognosis. Increased heterogeneity in cancers correlates with improved efficacy of checkpoint inhibitors, thought to be related to the prevalence of tumour specific or neoantigens acting as neodeterminants. HRD related ovarian cancers harbour more neoantigens and have increased tumour infiltrating lymphocytes. CeNtuRIOn is a multi-centre randomised study for patients with HRD ROC (PARPi alone versus or combinations of PARPi with antiPD-1 monoclonal antibody alone or also with additional antiCTLA4 monoclonal antibody. Aim: To collect archival / diagnostic, pre-treatment and post-treatment tissue from as many recruited patients as possible. To collect circulating tumour cells, plasma for ctDNA and serum for cytokine analysis from all recruited patients before, during and after study therapy. Methods: Archival diagnostic FFPE tissue will be collected for Next Generation Sequencing, pre-and post-treatment biopsies will also be sought from any patient that has recurrent ovarian cancer metastases accessible to image guided biopsy. Whole blood will be taken at various time-points before, during and after study therapy. This will be used to extract DNA from circulating tumour cells, isolate plasma for storage of ctDNA and extract serum for future cytokine analysis. How the results of the research will be used: The collected samples will be used to explore any changes in tissue and blood during PARPi +/- immunotherapy. Signatures in tissue / blood will be sought that might identify patients who will respond to such therapies in the future. Larger phase III trials will be used to confirm / refute these proposed hypotheses. Data from this sample collection will also allow sensible estimates of the types and numbers of patients required to show statistical significance for these hypotheses at Phase III.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS