Page 132 - Read Online

Page 666 Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002

DNA double-strand breaks. In patients with homologous recombination deficiency (HRD), including
patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with non-germline HRD-positive tumors,
inhibition of PARP results in production of double-strand breaks of DNA which cannot be effectively
repaired. Profound susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [6,7] spurred
the clinical development of this class of agents.

Sensitivity to platinum compounds is a feature of HRD, and a population of platinum-sensitive patients
is expected to be HRD-enriched and most likely to benefit from PARP inhibition. However, platinum
compounds damage DNA by several mechanisms, and cellular vulnerability to such drugs differs to
variable extents from vulnerabilities to PARP inhibitors (PARPis). In addition, combinations of existing
DNA-damaging drugs and PARPis, having undergone wide clinical testing, have yet to attain a therapeutic
role. The current review, therefore, with some exceptions, concentrates on the use of PARPis as single
agents and their emerging role in BRCA dysfunction related malignancies.

CHRONOLOGY OF PARP INHIBITOR DRUG DEVELOPMENT IN OVARIAN CANCER
PARP’s role in DNA damage repair, and its inhibition with 3-aminobenzamide (which competes with
[8,9]
the substrate of PARP), was a subject of study in the early 1980s . However, when such strategies were
explored in vivo, any improvement in the therapeutic index with the addition of 3-aminobenzamide
[10]
to alkylating drugs was far from certain . Nevertheless, seeking more potent PARPis than
3-aminobenzamide became the subject of structure-activity studies at Newcastle University, and
subsequently in collaboration with Agouron Pharmaceuticals, AG014699 (rucaparib) was selected for
pharmacologic and clinical studies by Calvert’s group [10-12] .

In 2005, two groups reported on the remarkable cytotoxicity of PARPis towards cell lines lacking BRCA
[7]
[6]
functionality, with Bryant et al. studying a close structural analogue to AG014699, and Farmer et al.
using a Kudos compound forerunner of AZD2281, olaparib. These findings led to the concept of exploiting
“synthetic lethality” - an example of how changes in two molecular pathways combine to have a lethal
[13]
effect on cells although neither of them is harmful individually. In 2008, Rottenberg et al. reported on
the efficacy of olaparib in BRCA1-deficient triple negative breast cancer mouse models, while the phase I
trial of this drug was ongoing. The findings in the phase I trial clearly demonstrated single agent activity
among patients with BRCA-mutated ovarian cancer. After expansion to include more patients with BRCA-
mutated ovarian cancer, there was a significant association with platinum sensitivity and response to
olaparib, across the platinum-sensitive, resistant and refractory subgroups, although responses were still
noted in platinum-resistant patients (and even in a couple of platinum-refractory patients) [Figure 1].
[14]
below. This study then led to a randomized trial of pegylated liposomal doxorubicin (PLD) and olaparib in
BRCA-mutated recurrent ovarian cancer that failed to show superiority for olaparib, perhaps because PLD
[15]
over-performed in these patients who recurred within one year of first-line treatment .

OVERVIEW OF TRIALS LEADING TO PARP INHIBITOR APPROVAL IN OVARIAN CANCER
After years in development, several PARPis have achieved indications in ovarian cancer treatment. The
approved roles of PARPis in ovarian cancer fall into two main approaches: treatment of recurrent disease
(the PARP inhibitor is used to shrink the tumor), and maintenance after response to platinum-based
chemotherapy. The approved roles of PARPis in ovarian cancer fall into two main approaches: treatment
of recurrent disease (the PARP inhibitor is used to shrink the tumor), and maintenance after response to
platinum-based chemotherapy. Table 1 summarizes clinically relevant PARP inhibitor ovarian cancer trials.

In the treatment of ovarian cancer, olaparib was the first PARPi to attain Food and Drug Administration
(FDA) approval, with much of the initial clinical investigation efforts concentrated on women with