Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial

Abstract

Background: In arm 1 of the phase II randomised OCTOPUS trial (ISRCTN16426935), no significant differences in Progression-Free Survival (PFS) or Overall Survival were observed with the addition of vistusertib (V), a dual mTORC1/2 inhibitor, to weekly paclitaxel (wP) in platinum-resistant/refractory ovarian high-grade serous carcinoma. However, preliminary immunohistochemistry (IHC) data suggested that PTEN status may be predictive of benefit of addition of V to wP. Aim: We evaluated if PTEN expression (scored using quantitative digital IHC) or specific genomic features might be predictive of V benefit. We also compared genomic profiles in archival and study entry specimens. Methods: PTEN expression in archival samples (N¼68) was scored using QuPath Histo-score (H-score; range 0-300), and compared to pathologist scoring. In archival (N¼43) and study entry (N¼35) samples, DNA copy number (CN) and CN signature exposure were assessed using shallow whole genome sequencing; target sequencing was performed using a custom panel (Illumina AmpliSeq). Results: Digital quantification of PTEN status was feasible with a high correlation between QuPath and pathologist scores (r¼0.94, p<0.0001 for tumour; r¼0.70, p¼0.009 for non-tumour). H-score variability was lower in non-tumour than in tumour cells. Patients with low PTEN tumours (defined as tumour<non-tumour H score) showed a longer PFS compared with those with PTEN proficient (tumour non tumour H-score) in the V+wP arm [respectively 9.4 vs 4.1 months (mo) p¼0.003] but not in the wP arm (4.8 vs 4.2 mo p¼0.60). There was no difference in overall ploidy, rates of focal somatic CN alterations or CN signature exposure between diagnosis and relapse. However, high exposure to CN signature 4 (defined as median signature 4 exposure across all samples) appeared associated with longer PFS (5.4 vs 3.3 mo p¼0.125) in the V+wP arm but worse outcome in the wP arm (2.3 vs 4.6 mo p¼0.018). Conclusions: PTEN loss by IHC and high exposure to CN signature 4 both appear to be associated with longer PFS in patients treated with V+wP. Validation in further sample sets will be required.