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Page 672 Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002

because it suggests that AML may be a toxicity specific to PARP inhibitor treatment, and not related to
[27]
prior chemotherapy, since these were patients treated in the frontline setting .

Rucaparib can cause significant anemia (19%-22% of patients with grade 3 or worse anemia) and
transaminitis (10%-12% of patients with grade 3 or worse transaminitis), but the transaminitis is rarely
symptomatic and bilirubin does not typically increase [21,24] . Olaparib’s most common grade 3 toxicity
is anemia, reported in 5%-22% of patients [22,33] , and to a lesser extent, the drug is also associated with
neutropenia. Niraparib more commonly causes thrombocytopenia than the other PARPis, with grade 3 or
4 thrombocytopenia reported in 34% of patients in the ENGOT-OV16/NOVA trial, although no patients
experienced grade 3 or 4 bleeding events. Grade 3 or worse anemia (25% of patients), neutropenia (20%),
[23]
and hypertension (8%) were also reported . The most frequent grade 3 or 4 toxicity for talazoparib was
anemia, which was reported by 39.2% of patients enrolled in EMBRACA . In EMBRACA, more patients in
[34]
the talazoparib arm experienced grade 3-4 adverse events than patients in the standard chemotherapy arm (in
contrast to olaparib in OlympiAD), although quality-of-life measurements were reassuring (talazoparib had
[34]
a significant delay in the time to deterioration in health compared to the standard chemotherapy arm) . A
phase 2 trial evaluating single agent veliparib in 50 recurrent ovarian cancer patients showed a low incidence
of grade 3 - 4 toxicities; the main grade 4 toxicity was thrombocytopenia in 2% of patients, and grade
3 adverse events were limited to fatigue in 6% of patients, nausea in 5% of patients, leukopenia in 2% of
[37]
patients, and neutropenia in 2% of patients .
Pharmacological features of the clinical PARPis are summarized in Table 2. We note that half-life informs
dosing schedule, and that drug-specific metabolic pathways (involving major cytochrome P450 enzymes)
tie into drug interactions.

ADDRESSING PARP INHIBITOR RESISTANCE
As indications for PARPis expand, and PARPis become incorporated into earlier lines of therapy, the issue of
PARP inhibitor resistance becomes increasingly important and one that a clinician caring for patients with
ovarian cancer will certainly have to face. There are several mechanisms of PARPi resistance, reflecting
the complex interplay of PARP enzymes with DNA repair, replication, and other pathways. The field is an
active area of research, and more resistance mechanisms are likely to emerge.

Mechanisms of PARP inhibitor resistance can be conceptualized as falling into one of a few categories:
restoration of HR, replication fork dynamics, PARylation balance, loss of PARP1, and drug efflux. Since
BRCA dysfunction is a key factor for the synthetic lethality of PARPis, reconstitution of BRCA protein and
restoration of HR was early on recognized as a cause of resistance to DNA damaging agents. Incomplete
data exists for PARP inhibitor resistance - but study of tumor organoids may be a way of addressing
this component of resistance. Another possible feature of such reversion of BRCA expression is that the
resistance to a PARP inhibitor may be clonal.

1. As noted above, restoration of HR: Restoration of HR abrogates the synthetically lethal effect of PARP
inhibition, and can therefore confer PARPi resistance. The development of BRCA reversion mutations
may be the most well described mechanism of HR restoration, and consequently also of PARPi resistance.
[56]
Norquist et al. evaluated 46 primary and recurrent ovarian cancer specimens from patients with a
history of germline BRCA mutations who were treated with platinum chemotherapy, and found that 28%
of the recurrent ovarian cancer specimens had reversion mutations which restored the functional BRCA
protein, compared to only 3% of the corresponding primary tumors. This percentage was significantly
higher in the platinum-resistant recurrent tumors compared to the platinum-sensitive recurrent tumors
(46% vs. 5%, P = 0.003). Another study evaluated patients with germline BRCA2 mutations and advanced