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

Abstract

Background Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA -mutated ( BRCA m) 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 ( BRCA wt) 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 BRCA m tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCA wt 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 BRCA m and BRCA wt tumours with BRCA1 methylation. Patients without BRCA m tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCA m 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 BRCA m.

Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial

“…Investigations into patients who were BRCAwt but deficient in other HRR genes are ongoing. 21 Study 19 was designed to demonstrate a statistically significant difference in PFS in the patients who were randomised: a population enriched for HRR tumours as a result of high-grade serous histology and platinum sensitivity. No rules were prespecified to control the Type 1 error rate for subgroups.…”

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

“…Recently, cancer genetic predisposition and precision medicine have found a contact point, thanks to the discovery of the therapeutic potential of PARP inhibitors in BRCA1/2 PV/LPV carriers [288,289], at first in OC [290] and then in BC, prostate, and pancreatic cancers [291][292][293]. PARP inhibitors have shown their efficacy, not only in patients with germline and somatic BRCA1/2 alterations [57], but also in patients with PV/LPVs in genes involved in the HR pathway with BRCA1 and BRCA2 proteins [294][295][296][297], and clinical trials are currently addressing this [136]. These results pave the way for the future use of PARP inhibitors in all tumors with a deficiency of the HR system, independently of the germline or somatic nature of the alteration.…”

Inhibition of c‐MET increases the antitumour activity of PARP inhibitors in gastric cancer models

“…It is known that BRCA deficiency causes problems in the DNA damage repair mechanism. Tumours with mutant BRCA genes are more sensitive to PARP inhibition 22,54 . Therefore, it is interesting to consider whether dual inhibition of PARP and c‐MET using NU1074 and SU11274 inhibitor, respectively, reveals a proficient beneficial effect for BRCA deficiency gastric malignancies.…”