Title: CRUKDE/17/017 CeNtuRIOn: An open-label, randomised, phase II trial of ruCaparib combined with Nivolumab +/- Ipilimumab to augment response in homologous repair deficient patients with relapsed Ovarian cancer
Funder: Cancer Research UK

Abstract: Background: Patients with ovarian cancer are initially very responsive to platinum but 90% become resistant and 5 year survival in this group remains poor at ~36%. The median progression-free survival (PFS) for relapsed ovarian cancer (ROC) patients in this study 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. Extensive genome-wide loss of heterozygosity (LoHHIGH) has been shown to identify BRCAwt ROC patients that probably have HRD and are thus likely to respond to PARPi. 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. Aims: To explore whether combining checkpoint inhibitors with a PARPi in patients with HRD associated ROC will improve efficacy as measured by PFS. Methods: A multi-centre study randomising patients with HRD ROC to PARPi alone (rucaparib=R) or combinations of either R and nivolumab (antiPD-1 monoclonal antibody=N) or R, N and ipilimumab (antiCTLA4 monoclonal antibody=I). Safety/toxicity will be checked in an initial cohort of 12-18 patients. If acceptable, 234 patients will be randomised (1:1:1): R versus RN versus RNI to determine PFS intervals. Secondary outcomes include response rate, OS and quality of life. Translational samples (blood and tissue) will be collected at baseline, during and after treatment for biomarker exploration. How the results of the research will be used: The results of this trial will be used to design large international Phase III trials to better demonstrate the efficacy of combination PARPi with immunotherapy in HRD ROC. CeNtuRIOn will enable better estimates of the types and numbers of patients required to show statistical significance at Phase III. It will also generate an understanding of changes in tissue and blood that might predict a response so that similar biomarkers in the phase III trials can confirm/refute these hypotheses.

Lay abstract: Background: Patients with ovarian cancer are initially very responsive to platinum but 90% become resistant and 5 year survival in this group remains poor at ~36%. The median progression-free survival (PFS) for relapsed ovarian cancer (ROC) patients in this study 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. Extensive genome-wide loss of heterozygosity (LoHHIGH) has been shown to identify BRCAwt ROC patients that probably have HRD and are thus likely to respond to PARPi. 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. Aims: To explore whether combining checkpoint inhibitors with a PARPi in patients with HRD associated ROC will improve efficacy as measured by PFS. Methods: A multi-centre study randomising patients with HRD ROC to PARPi alone (rucaparib=R) or combinations of either R and nivolumab (antiPD-1 monoclonal antibody=N) or R, N and ipilimumab (antiCTLA4 monoclonal antibody=I). Safety/toxicity will be checked in an initial cohort of 12-18 patients. If acceptable, 234 patients will be randomised (1:1:1): R versus RN versus RNI to determine PFS intervals. Secondary outcomes include response rate, OS and quality of life. Translational samples (blood and tissue) will be collected at baseline, during and after treatment for biomarker exploration. How the results of the research will be used: The results of this trial will be used to design large international Phase III trials to better demonstrate the efficacy of combination PARPi with immunotherapy in HRD ROC. CeNtuRIOn will enable better estimates of the types and numbers of patients required to show statistical significance at Phase III. It will also generate an understanding of changes in tissue and blood that might predict a response so that similar biomarkers in the phase III trials can confirm/refute these hypotheses.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS