Olaparib is a PARP inhibitor approved in Europe as maintenance treatment after response to platinum-based chemotherapy in patients (pts) with relapsed, epithelial ovarian cancer (EOC) who harbour a mutation in BRCA. Approval was based on the results of study 19 (NCT00753545). We tested whether TP53 mutations categorized according to their functional effects influence overall survival (OS) in a cohort of 195 EOC pts randomized to olaparib or placebo after platinum-based chemotherapy in study 19.
TP53 status was assessed in anonymized archival tumor samples at Foundation Medicine.TP53 mutations were classified, blinded to treatment and clinical outcome, as “disruptive” (D) and “non disruptive” (ND) according to the degree of disturbance of p53 protein function and structure. Particularly, TP53 (D) mutations are associated with a severe disturbance in the DNA repair activities of the p53 protein. Overall survival (OS) and progression-free survival (PFS) were explored by TP53 and BRCA mutation status. Data cut-off was May 2016.
95 pts had TP53(D) and 100 pts TP53(ND) tumours. Hazard ratios (HR) for PFS in the overall, BRCAm and BRCAwt populations were comparable between TP53(D) and TP53(ND). Pts with TP53(D) derived a statistically significant benefit from olaparib treatment, with median OS of 39.5 months (m) for olaparib and 24.0 m for placebo and a HR = 0.57 (95%CI = [0.35, 0.92]) versus HR = 0.73 (95%CI = [0.46, 1.15]) in the case of pts with TP53(ND). When including BRCA status in the analysis; all pts with BRCA mutations (n = 108) derived a benefit from olaparib in terms of OS, irrespective of TP53 status. In the BRCA wt group, pts with TP53(D) treated with olaparib had an OS of 35.0 m vs. 25.5 m for those receiving placebo (n = 47, HR = 0.80 [0.40, 1.52]). Finally, only pts with TP53(ND) and BRCAwt did not derive any benefit in median OS from olaparib treatment (n = 40, HR = 1.58 [0.77, 3.35]).
EOC patients BRCA wt with TP53 disruptive mutations may derive a survival benefit of olaparib treatment. Further studies are required to confirm this finding.
Clinical trial identification
Legal entity responsible for the study
Instituto Oncologico Dr Rosell. Astra Zeneca
A. Fielding, B.A. Dougherty, Z. Lai, D. Hodgson, P. Rowe, S. Spencer, A. Gasco Hernandez: Astra Zeneca employee J. Lobera: Astra Zeneca All other authors have declared no conflicts of interest.