P3.15-008 [F18]PARPi PET as an In Vivo Pharmacodynamic Biomarker of PARP Inhibitor Therapy in Patient-Derived Xenografts of Small Cell Lung Cancer

Abstract

Inadequate drug delivered to target tumors contributes to ineffective treatment. However, the delivered drug concentration is difficult to assess in patients in a timely and clinically-relevant manner. To address this barrier to PARP inhibitor (PARPi) therapy, we evaluated a radiolabeled PARP inhibitor ([F18]PARPi) as a pharmacodynamic biomarker. We hypothesized that [F18]PARPi PET imaging can measure PARP inhibitor concentration and activity intratumorally, thereby, predicting therapeutic efficacy. Here, we applied this approach to patient-derived xenografts (PDX) of small cell lung cancer (SCLC). To study [F18]PARPi PET as a biomarker of talazoparib (TAL), SCRX-Lu149 PDXs were orally gauged with different doses of TAL. Mice were injected with [F18]PARPi and imaged with PET, with the expectation that TAL would competitively block [F18]PARPi binding to PARP. Organ retrieval and gamma counting was performed for drug and radiotracer biodistribution. Ex vivo PARP enzymatic activity was measured by ELISA of PAR levels. Differences in PET uptake and the tumor volumetric endpoint (time to reach 1000 mm3) were analyzed by student t-test and the log-rank test, respectively. In PK PET imaging with 0.2 mg/kg TAL, greatest blocking of the radiotracer was noted at 1 hour after gavage with less blocking as time from dosing was extended (avg of 3 mice: 4.5, 2.2, 2.7, 3.1, and 3.4% max injected dose per gram [ID/g] for untreated, 1, 3, 6, and 24 h after drug, respectively). [F18]PARPi PET differentiated between doses of 0.1 and 0.3 mg/kg TAL at 3 h after dosing (3.9 vs 2.1% ID/g or 13% vs 53% relative blocking, respectively; p=0.003). No differences were noted in heart, lung, esophagus, muscle, or bone. PET uptake correlated with ex vivo enzymatic inhibition/PAR levels (p=0.0009). PET measured differences in drug doses corresponded with improved outcomes for PDXs treated with 0.3 mg/kg in combination with radiotherapy (RT; median 84 days, p=0.04) but not 0.1 mg/kg + IR (66 days) compared to RT alone (52 days). [F18]PARPi PET can differentiate between multiple doses and timing of orally administered TAL and correlates with drug efficacy. This likely reflects differences in intratumoral drug level and demonstrates the potential of this PET radiotracer to assess differences in drug delivery and efficacy for patients treated with PARP inhibitors.