Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

Darren R Hodgson,Jonathan Ledermann,Alexander Gutin,Tony W Ho,Chris Womack,J Carl Barrett,Anitra Fielding,Lynda Grinsted,Maria Orr,Mark J O’Connor,Blake Gilks,Helen Jones,Stuart Spencer,Brian A Dougherty,Kirsten M Timms,Jane D Robertson,Jerry S Lanchbury,Zhongwu Lai,Charlie Gourley

doi:10.1038/s41416-018-0274-8

Abstract

BackgroundOlaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours.MethodsTumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score.ResultsPatients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients.ConclusionsOvarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

Highlights

Olaparib (LynparzaTM) is a Poly(ADP-ribose) polymerase (PARP) inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer
The specific homologous recombination repair (HRR) mutations identified in the 21 tumour samples were: BRIP1 (n = 5), CDK12 (n = 3), RAD54L (n = 2), RAD51B (n = 2), RAD54L rearr (n = 1), ATM rearr (n = 1), FANCA rearr (n = 1), FANCD2 (n = 1), FANCL rearr (n = 1), FANCL (n = 1), RAD51C (n = 1), RAD52 del (n = 1), XRCC3 rearr (n = 1) (Fig. 1)
Deficiencies in other proteins involved in homologous recombination conferred sensitivity to PARP inhibition, albeit with a lesser impact than BRCA deficiency[5] and high-grade serous ovarian cancer (SOC) was initially thought to represent a promising tumour type for PARP inhibitor therapy because, in addition to a high frequency of BRCA mutations, it is characterised by large-scale genomic instability and repeated, durable platinum sensitivity

Summary

Introduction

Olaparib (LynparzaTM) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo to a lesser extent than BRCAm patients. CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm

Methods

Results

Discussion

Conclusion