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Page 670 Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002
[37]
response rate compared to platinum sensitive patients (20% vs. 35%, respectively) .

[38]
Talazoparib is the most potent PARP trapper of the PARPis , and is being actively evaluated in several
clinical trials. The drug is being evaluated in the neoadjuvant setting as a single agent for triple negative
breast cancer, as a single agent for advanced solid tumors, in combination with temozolamide in the
treatment of recurrent small cell lung cancer, alone and in combination with enzalutamide in metastatic
prostate cancer, and in combination with immunotherapy (avelumab, in untreated advanced ovarian
cancer) and chemotherapy [clinicaltrials.gov].

Other PARPis are in early clinical development. The PARP 1/2 and Tanykyrase 1/2 inhibitor E7449 was
evaluated in a phase 1 clinical trial as monotherapy for patients with advanced solid tumors, and showed
[39]
evidence of antitumor activity with low toxicity . CEP-9722 is another PARP 1/2 inhibitor which was
evaluated in a phase 1 dose-escalation trial alone and in combination with temozolomide in patients
[40]
with advanced solid tumors, and showed only limited clinical activity but acceptable tolerability . CEP-
9722 was also assessed in combination with gemcitabine and cisplatin in a small dose escalation study in
patients with advanced solid tumors or mantle cell lymphoma, but the study was discontinued early due to
[41]
toxicities (mainly chemotherapy associated myelosuppression) .
In 2011, there was initial excitement about the putative PARP inhibitor iniparib following encouraging
results from a phase 2 trial that evaluated the drug in combination with chemotherapy in the treatment
of triple negative breast cancer, but the subsequent phase 3 trial failed to demonstrate any statistically
significant PFS or OS benefit . Trials evaluating iniparib in other cancers and in vitro studies later
[42]
[43]
indicated that iniparib does not does not function as a true PARP inhibitor .

SPECIFIC DRUG FEATURES
PARP function, inhibitor targets, and PARP trapping
PARP enzymes catalyze poly-ADP-ribosylation (PARylation) of nuclear proteins, including themselves.
Rapid PARylation at DNA damage sites is a pivotal component of the cell’s DNA damage response. Base
excision repair is one of several pathways involved in the repair of single-strand DNA breaks, and relies on
PARylation to recruit DNA repair complexes to the site of the break [44,45] .

PARP1 is also involved in maintaining genomic stability through the regulation of double-strand DNA
repair processes, including the error-prone nonhomologous end-joining and microhomology-mediated
[2,5]
end-joining processes . More specifically, in vitro studies have found that PARP1 functions in the
microhomology-mediated end-joining pathway, and that inhibition or depletion of proteins involved in
this pathway, including PARP1, is synthetically lethal in cells with HRD [46,47] . This suggests that another
mechanism for PARPi/HRD synthetic lethality is the simultaneous loss of HR and microhomology-
[4]
mediated end-joining . Overall, inhibition of PARP can induce genomic instability by shifting the balance
of several DNA repair processes, which may be synthetically lethal in HRD cells.

The major substrate for the PARP enzymes is NAD+. PARPis compete with NAD+ for the PARP
catalytic site. The resulting PARP inhibition affects DNA repair not just through inhibition of PARP’s
catalytic activity, but also by interfering with PARP’s ability to disassociate from the damaged DNA,
which is termed PARP trapping. In vitro studies found that PARP trapping is more cytotoxic than
[48]
unrepaired single-strand breaks caused by PARP depletion , conceivably because trapped PARP is more
likely to cause stalled replication forks and double-strand DNA breaks . Thus, PARP trapping is another
[49]
explanation for the synthetic lethality of PARP inhibition in tumors with HRD.