An analysis of data from a phase II trial comparing olaparib to placebo showed that olaparib yielded improved overall survival (OS) in all patients with mutated BRCA irrespective of the TP53 status and also in patients with BRCA wild-type in tandem with disruptive mutations in the TP53 DNA repair gene, according to findings presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Lead author Alejandro Martinez Bueno, Medical Oncology, Instituto Oncologico Dr Rosell, Hospital Quirón in Barcelona, Spain and colleagues evaluated the TP53 status (disruptive versus non-disruptive) and the relationship to OS in a cohort of 195 patients with ovarian cancer receiving olaparib or placebo after platinum-based chemotherapy. The OS and progression-free survival (PFS) were investigated according to TP53and BRCA mutation status.
Olaparib is an inhibitor of PARP, which is important for repairing single strand DNA breaks. During cell division, these may become double strand breaks, which are lethal to cells. Some types of tumour cells have a deficiency in the homologous recombination pathway that can repair double stranded breaks, for example mutations in the BRCA1 and BRCA2, which may allow cells with faulty DNA to survive.
The investigators used data and anonymous archival tumour samples located at Foundation Medicine from NCT00753545 study.TP53status was assessed as disruptive or non-disruptive according to the degree of disturbance of p53 protein function and structure. Specifically, disruptive TP53 mutations associate with a severe disturbance in the DNA repair activities of the p53 protein.
An OS benefit with olaparib was shown across all subgroups excepting patients harbouring BRCA wild-type, TP53 non-disruptive
At data cut-off in May 2016, the investigators determined that 95 patients had TP53 disruptive mutations and 100 patients had TP53 non-disruptive tumours.
No significant PFS benefit was seen the in the analysis of both BRCA mutated and BRCA wild-type populations, which revealed comparable hazard ratios [HR] for PFS between TP53 disruptive and TP53 non-disruptive subgroups.
However, the comparison of disruptive to non-disruptive TP53 according to BRCA status told a different story regarding OS.
Patients having TP53 disruptive mutation showed a statistically significant OS benefit from olaparib; these patients demonstrated median OS of 39.5 months with olaparib compared to 24.0 months with placebo, HR 0.57 (95% confidence interval [CI] 0.35, 0.92) versus patients with TP53 non-disruptive, HR 0.73 (95%CI 0.46, 1.15).
An analysis of BRCA status showed that all 108 patients with BRCA mutations had an OS benefit with olaparib that was independent of TP53 status, although this benefit seemed stronger in TP53 disruptive (18 vs 7.5 months)
Patients with TP53 disruptive mutations in the BRCA wild-type group treated with olaparib demonstrated OS of 35.0 months compared to 25.5 months for similar patients on placebo (n=47, HR 0.80 [95% CI 0.40, 1.52]).
Only the mutational subgroup of 40 patients with BRCA wild-type and TP53 non-disruptive mutation did not derive benefit from olaparib treatment, HR 1.58 (95% CI 0.77, 3.35).
However, authors stand out that the number of patients/events for some of the subgroups are low and further validation is needed in larger patient population.
The NCT00753545 study results provided the basis for olaparib to be approved in Europe as maintenance treatment after response to platinum-based chemotherapy in patients with relapsed, epithelial ovarian cancer who harbour a BRCA mutation.
In the overall patient population TP53 disruptive mutations attained a significant OS benefit from olaparib treatment. All BRCA mutated patients experienced better OS regardless TP53 status, although OS was longer for TP53 disruptive mutations (18 vs 7.5 months). For BRCA wild-type patients, only TP53 disruptive patients might achieve longer OS with olaparib. The results of this post-hoc exploratory analysis should be interpreted with caution and further validation in larger patient population is needed.
No external funding was reported for this analysis.
LBA42 – Martinez Bueno A, et al. Disruptive mutations in TP53 associate with survival benefit in a PARPi trial in Ovarian Cancer.