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.
These data support the further clinical investigation of ZD 1839. The elimination half-life suggests that once daily oral administration is appropriate.
Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.
This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).
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