PARP Inhibitor Therapy

One of the highest growing therapy categories in precision medicine has been with PARP inhibitors (PARPi), which block the cancer cell’s ability to use the PARP enzyme to repair the high levels of DNA damage present in cancer cells. Collectively, the PARPi market is projected to be $8 billion worldwide by 2027* and four PARPi’s are currently approved in the US as treatment for patients with breast, prostate, ovarian, pancreatic cancers, and in clinical trials with other cancer indications.

The PARPi binds to the damaged DNA in the tumor cell nucleus cell pocket (NAD+), preventing the cell from repairing breaks in the damaged DNA strand with PARP-1 enzymes. Conventional PARPi therapy has assumed that two conditions need to exist for PARPi therapy to be successful:
1) The homologous repair mechanism (most commonly seen in mutated BRCA genes that use the undamaged strand to replicate itself and repair the damaged DNA) must be broken via DNA damaging chemotherapy and
2) PARPi’s must be used to block the cell’s ability to use the PARP enzyme to repair breaks in the damaged DNA strand.
This dual condition is called “synthetic lethality” which results in cancer cell death.

This treatment approach requires use of genomic assays (both tissue and blood) to identify patients with BRCA mutations or other homologous repair defects (HRD) as appropriate candidates for PARPi therapy. To date, there is no clinically effective way to determine whether a tumor is a PARP-1 tumor or whether the tumor cell would demonstrate high PARPi uptake.

Furthermore, early clinical results have shown that patients with BRCA mutations can exhibit differing levels of PARP-1 uptake (as imaged by [¹⁸F]FTT) and conversely, patients without the BRCA or HRD mutations sometimes exhibit high levels of PARP-1 uptake. These situations suggest that
a) high PARP-1 uptake shown by [¹⁸F]FTT could indicated PARPi efficacy in non-BRCA/HRD patients and would open up a larger market for PARPi therapy, and
b) low PARP-1 uptake in BRCA/HRD patients could indicate that PARPi therapy would not be successfully, thereby saving patient potential toxicity of treatment and large medical expense.