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Clinical Trial
. 2018 Nov;119(11):1401-1409.
doi: 10.1038/s41416-018-0274-8. Epub 2018 Oct 24.

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

Darren R Hodgson  1 , Brian A Dougherty  2 , Zhongwu Lai  2 , Anitra Fielding  3 , Lynda Grinsted  3 , Stuart Spencer  3 , Mark J O'Connor  3 , Tony W Ho  4 , Jane D Robertson  3   5 , Jerry S Lanchbury  6 , Kirsten M Timms  6 , Alexander Gutin  6 , Maria Orr  3 , Helen Jones  3 , Blake Gilks  7 , Chris Womack  8 , Charlie Gourley  9 , Jonathan Ledermann  10 , J Carl Barrett  2
Affiliations
Clinical Trial

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

Darren R Hodgson et al. Br J Cancer. 2018 Nov.

Abstract

Background: Olaparib (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.

Methods: Tumour 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.

Results: Patients 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.

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.

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Conflict of interest statement

D.R.H., B.A.D., Z.L., A.F., L.G., S.S., M.J.O.C., T.W.H., M.O., H.J. and J.C.B. are AstraZeneca employees and stockholders; J.D.R. and C.W. were AstraZeneca employees and stockholders at the time the study was conducted. J.S.L., K.M.T. and A.G. are Myriad Genetics Inc. employees and stockholders; C.G. has acted in an advisory role for AstraZeneca, Clovis, Roche and Nucana, received honoraria from AstraZeneca and Roche, and received research funding from AstraZeneca, Novartis and Aprea; J.L. has participated in an advisory board for AstraZeneca; B.G. declares no competing interests.

Figures

Fig. 1
Fig. 1
HRR gene mutations that are mutually exclusive to BRCA1/2. Each column represents one patient from whom tumours were sequenced (n = 209)
Fig. 2
Fig. 2
PFS and OS by BRCA and HRR status determined at the time of Study 19 and in the exploratory subgroups defined by the Foundation Medicine analysis. *P < 0.05, **P < 0.01, ***P < 0.001. BRCAm BRCA mutation, BRCAwt BRCA wild type, CI confidence interval, HR hazard ratio, HRRm homologous recombination repair gene mutation, HRRwt homologous recombination repair genes wild type, n number of patients, OS overall survival, PFS progression-free survival, tBRCAm tumour BRCA mutation, tBRCAwt tumour BRCA wild type. Three patients who were classified as tBRCAwt following Foundation Medicine analyses were found to Have BRCAm following germline analysis
Fig. 3
Fig. 3
PFS and OS by BRCA and HRR status determined at the time of Study 19 and in the exploratory subgroups defined by the Myriad MyChoice HRD score analysis. **P < 0.01, ***P < 0.001. BRCAm BRCA mutation, BRCAwt BRCA wild type, CI confidence interval, HR hazard ratio, HRD homologous recombination deficiency, ITT intention to treat, n number of patients, OS overall survival, PFS progression-free survival, tBRCAm tumour BRCA mutation, tBRCAwt tumour BRCA wild type
Fig. 4
Fig. 4
Summary of Myriad MyChoice HRD scores. Patients must be evaluable for both Myriad HRD score and mutation/methylation status to be included. BRCAwt BRCA wild type, HRD homologous recombination deficiency, HRRm homologous recombination repair gene mutation, HRRwt homologous recombination repair genes wild type, n number of patients, tBRCAm tumour BRCA mutation
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References

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