P5-10-01: Metabolic Pharmacodynamic Effect Evidenced by 18FDG-PET as a Tool for Early Prediction of Iniparib Efficacy in Metastatic Triple Negative Breast Cancer (MTNBC): A Proof of Concept Study.

Rationale : It was hypothesised that Iniparib or 4-iodo-3-nitrobenzamide acts as an irreversible inhibitor of PARP1 and possibly other enzymes. It has shown successively promising then confusing results in MTNBC in combination with chemotherapy. To date, its mechanism of action has not been completely elucidated but since 1992, inhibition of glycolysis by iniparib and subsequent necrotic cell death has been described. We hypothesised that early inhibition of glycolysis evidenced by in-vivo imaging with 2-((18)F)Fluoro-2-Deoxy-D-Glucose Positron-Emission Tomography (18FDG-PET) may be a predictor of efficacy to iniparib, as it was previously reported for other anticancer drugs. Objectives : To detect metabolic pharmacodynamic effect of iniparib plus chemotherapy by means of 18FDG PET and proof the concept of its use as an early predicitive tool of Iniparib efficacy in MTNBC. Patients & Methods : From March to November 2011, 8 pts were included in our institution in a randomized phase II study comparing bi-weekly versus weekly iniparib treatement in combination with gemcitanine and carboplatin. All patients had 18FDG-PET at baseline, at day 7 (D7). The maximum value of standardized uptake value (SUVmax) of all measurable metastatic lesions was measured and the median SUVmax was calculated for all patients at baseline and D7. The metabolic response was defined as the percentage of reduction of SUVmax (SUVmax Baseline — SUVmax D7) / SUVmax Baseline and the median SUVmax response was correlated to RECIST 1.1 response at six weeks and to disease-free survival (DFS). Results : The median decrease in SUVmax of evaluable lesions measured at D7 was predictive of RECIST 1.1 response at six weeks and was correlated to the best obtained response during the treatment phase. Furthermore, it showed a linear correlation with DFS (y = −0,0007x - 0,1325; R 2 = 0,3402). Conclusion : Metabolic pharmacodynamic effect as evidenced by 18FDG PET as soon as one week of treatement act as an early predicitive tool of Iniparib plus chemotherapy efficacy in MTNBC. Considering the lack of a predicitive biomarker of response and if confirmed on larger study, 18FDG PET could be used as a surrogate predictive biomarker is this setting. These results may be considered as an in-vivo proof of concept for the inhibition of glycolysis by iniparib. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-10-01.