Imaging Pharmacodynamics of a PARP Inhibitor

Take-Away Points

• ■ Major Focus: To establish the feasibility of PET imaging with fluorine 18 (¹⁸F)–FluorThanatrace (FTT) to detect binding of an inhibitor of a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib, in patients with breast cancer.

• ■ Key Result: Treatment with a PARP inhibitor in patients with metastatic breast cancer blocked binding of ¹⁸F-FTT to the PARP enzyme.

• ■ Impact: ¹⁸F-FTT may be used to noninvasively image pharmacodynamics of therapy with PARP inhibitors in vivo.

PARPs are a family of enzymes involved in structure and repair of DNA. Inhibitors of PARP enzymes are used clinically in patients with breast cancer who have mutations in the breast cancer susceptibility genes BRCA1/2. However, BRCA1/2 mutations do not fully predict response to PARP inhibitors. Some patients with mutations fail to benefit from treatment, while treatment may be effective even without mutations in BRCA1/2. Variability in response highlights the need for a biomarker to predict response to treatment with a PARP inhibitor.

In a small prospective clinical study, McDonald et al used ¹⁸F-FTT, a PET radiotracer that binds to PARP enzymes, to monitor response to therapy with a PARP inhibitor administered to patients with metastatic breast cancer. Pretreatment images showed heterogeneous uptake of ¹⁸F-FTT in metastases, showing that amounts of PARP differ notably in different lesions within in a patient. Follow-up imaging after therapy with a PARP inhibitor reduced uptake of ¹⁸F-FTT to background levels. Laboratory studies on tumor tissue from several patients verified that a clinical PARP inhibitor blocked binding of the radiotracer to PARP.

The current study analyzed data qualitatively rather than quantitatively, and future studies will need to correlate imaging with patient outcomes or other metrics of response. Despite these limitations, the study establishes an imaging approach to monitor pharmacodynamics of a molecularly targeted therapy in patients with cancer.

Highlighted Article

• McDonald ES, Pantel AR, Shah PD, et al. In vivo visualization of PARP inhibitor pharmacodynamics. JCI Insight 2021;6(8):e146592. doi: https://doi.org/10.1172/jci.insight.146592.