Discussion
TNBC, cancers
CANCERS, RECRUITMENT
We report Cohort E of the plasmaMATCH study, a single group phase II study in patients with TNBC. The response rate to olaparib and ceralasertib did not meet prespecified criteria for efficacy in the overall evaluable population. However, additional biomarker work identified a number of potential predictive biomarkers, which could be investigated in future clinical trials.Patients with germline and also somatic Our study has a number of limitations. As a non-comparative phase II study we are unable to assess whether activity observed is a result of the combination therapy, or one of the individual drugs in the combination. In the recently presented VIOLETTE study (NCT03330847) patients with metastatic TNBC were randomized to receive olaparib, olaparib, and ceralasertib or olaparib and adavosertib (Entry into Cohort E of plasmaMATCH was for patients who did not have actionable mutations in their ctDNA, or if no cohort was available, and this may have led to bias in patient recruitment. However, the cohort commenced late in the trial, the majority of patients were enrolled once other cohorts had stopped recruitment, and the patient population enrolled in Cohort E was likely overall reflective of unselected metastatic TNBC. Prior research has suggested that ATR inhibitors may have substantial efficacy in ATM-deficient cancers, yet in Cohort E we do not see strong evidence for activity in cancers with absent/low ATM expression. This may be reflective of selection on the basis of protein ATM expression, instead of selecting on the basis of ATM inactivating mutations, and/or may reflect the schedule of ATR inhibitor employed, with potentially more continuous schedules being more optimal for ATM-deficient cancers.In conclusion, we report here the result of a large phase II study in advanced TNBC with olaparib plus ceralasertib therapy. The study did not observe sufficient evidence of efficacy by the predefined criteria, and this is broadly in line with the data observed in the randomized phase II VIOLETTE study (