Abstract
Purpose: PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) highgradeserousovariancancer(HGSOC).However,notallHRDtumors respond to PARPi. Biomarkers to predict response are needed. [18F]FluorThanatrace([18F]FTT)isaPARPi-analogPETradiotracer thatnoninvasivelymeasuresPARP-1expression.Herein,weevaluate [18F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC. Experimental Design: In PDX models, [18F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [18F]FTT were correlated with tumor volume changes. Subjects were imaged with [18F]FTT-PET at baseline and after ~1 week of PARPi. Changes in [18F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS). Results: A decrease in [18F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r ¼ 0.77–0.81). In subjects (n ¼ 11), percent difference in [18F]FTT-PET after ~7 days of PARPi compared with baseline correlated with best RECIST response (P ¼ 0.01), best CA-125 response (P ¼ 0.033), and PFS (P ¼ 0.027). All subjects with >50% reduction in [18F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [18F]FTT uptake did not predict such responses. Conclusions: The decline in [18F]FTT uptake shortly after PARPi initiation provides a measure of drug-target engagement and shows promise as a biomarker to guide PARPi therapies in this pilot study. These results support additional preclinical mechanistic and clinical studies in subjects receiving PARPi ± combination therapy. See related commentary by Liu and Zamarin, p. 1384.
Original language | English (US) |
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Pages (from-to) | 1515-1527 |
Number of pages | 13 |
Journal | Clinical Cancer Research |
Volume | 29 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2023 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research