Review Article

PARP Inhibitors in Breast Cancer: Bringing Synthetic Lethality

to the Bedside
Anita A. Turk, MD; and Kari B. Wisinski, MD

Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased
lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA.
In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) poly-
merase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while
sparing normal cells—a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit syn-
thetic lethality. Recent clinical trials in BRCA-mutant, metastatic breast cancer demonstrated improved outcomes with single-agent
PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily
due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemo-
therapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of
PARP inhibitors in BRCA-mutant breast cancer and potential future directions for these agents. Cancer 2018;000:000-000. V C 2018

American Cancer Society.

KEYWORDS: breast cancer, breast and ovarian cancer susceptibility gene (BRCA)-mutant, DNA repair, hereditary, poly(adenosine
diphosphate-ribose) polymerase (PARP).

BRCA1/BRCA2 MUTATIONS IN BREAST CANCER

Most breast cancers are sporadic, and only 5% to 10% are classified as hereditary. Germline mutations in breast and ovar-
ian cancer susceptibility gene 1 (BRCA1) or BRCA2 result in hereditary breast and ovarian cancer syndrome. The BRCA1
gene, located on chromosome 17, was first identified and cloned in 1994.1 Subsequently, BRCA2 was identified on chro-
mosome 13.2 These tumor suppressor proteins function in the homologous recombination (HR) repair of double-
stranded DNA breaks. The HR-repair mechanism protects the integrity of the genome in proliferating cells during the S
and G2 phases of the cell cycle. BRCA1 has multiple functions in DNA repair, including recognition of DNA damage,
checkpoint activation, and recruitment of DNA-repair proteins. BRCA2 mediates the recruitment of RAD51 recombi-
nase (RAD51) to double-stranded DNA breaks to allow for HR repair.3
Alterations in BRCA1 and BRCA2 lead to a highly penetrant, autosomal dominant predisposition to breast cancer,
with lifetime estimates as high as 84%.4 BRCA1 and BRCA2 mutations do result in different clinical phenotypes. Breast
cancer risk begins to rise at younger ages for BRCA1 mutation carriers compared with BRCA2 carriers.5 BRCA1-mutant
breast cancers are more often high grade, triple negative (TNBC) cancers (negative for estrogen receptor, progesterone
receptor, and human epidermal growth factor receptor 2 [HER2]) and have a basal epithelial phenotype; whereas BRCA2-
mutant breast cancers more often exhibit a luminal B phenotype with expression of hormone receptors that have higher
Oncotype Dx recurrence scores compared with sporadic tumors.6-8 The National Comprehensive Cancer Network guide-
lines recommend genetic testing for all patients aged 60 years who have TNBC, because 15% to 33% of these individu-
als will have an abnormal gene mutation.9,10

MECHANISM OF POLY(ADENOSINE DIPHOSPHATE-RIBOSE) POLYMERASE

Poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) is a family of enzymes, and the PARP1 and PARP2 iso-
forms have a key role in base excision repair (BER) in response to single-stranded DNA breaks.11,12 In response to DNA
damage, the zinc-finger DNA-binding domains localize PARP-1 and PARP-2 to the site of DNA damage. PARP enzymes
then cause posttranslational modification with the addition of ADP-ribose to target nuclear proteins.13-15 There is also

Corresponding author: Kari B. Wisinski, MD, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, WIMR 6033, Madison, WI 53705-2275;
kbwisinski@medicine.wisc.edu

University of Wisconsin Carbone Cancer Center, Madison, Wisconsin

DOI: 10.1002/cncr.31307, Received: December 12, 2017; Revised: January 30, 2018; Accepted: February 2, 2018, Published online Month 00, 2018 in Wiley
Online Library (wileyonlinelibrary.com)

Cancer Month 00, 2018 1

Review Article

Figure 1. Synthetic lethality is illustrated. A single-strand DNA break (SSB) leads to poly(adenosine diphosphate-ribose) polymer-
ase (PARP) recruitment and activation. PARP inhibition and trapping on DNA results in persistent SSBs and stalling of replication
forks. This leads to double-strand DNA breaks (DSBs), which require homologous recombination (HR) for repair. In breast cancer
(BRCA)-mutant cancer cells, loss of heterozygosity leads to nonfunctional BRCA, and HR repair cannot occur. This ultimately
results in cell death. Normal cells retain a functional BRCA protein and can repair DSBs, resulting in cell survival. NHEJ indicates
non-homologous end joining.

evidence to suggest a role of PARP in restarting stalled CLINICAL DEVELOPMENT IN BREAST

DNA-fork replication and BRCA1/BRCA2-mediated
homologous recombination.16
When PARP is inhibited, single-strand breaks per-
sist and result in stalled replication forks and double-
strand breaks. PARP function is impeded by PARP inhib-
itors (PARPis), resulting in catalytic inhibition, and some
also trap PARP on DNA. These PARP-DNA complexes
interfere with DNA replication, and recent studies have
indicated that PARP trapping is important for the cyto-
toxicity of PARPis.17 BRCA-mutant tumors develop HR
deficiency secondary to germline mutation in 1 allele and
loss of heterozygosity, inactivating the other copy. Treat-
ment of these tumors with a PARPi leads to an accumula-
tion of DNA damage, resulting in cell-cycle arrest and
apoptosis.18-20 This effect of PARP inhibition in cells that
have defects in the HR pathway is an example of synthetic
lethality (Fig. 1). Increased PARP activity is also one of the
mechanisms by which tumor cells avoid apoptosis caused
by DNA-damaging chemotherapy agents, which nor-
mally would be repaired through the BER system. There-
fore, the inhibition of PARP sensitizes tumor cells to
cytotoxic agents, such as alkylators and topoisomerase I
inhibitors.21,22
CANCER
Several PARPis are being studied in BRCA-mutant breast
cancer. The clinical application of PARPis has progressed
under 2 strategies: PARPi monotherapy in malignancies
with impaired DNA-damage repair pathways and PARPis
combined with DNA-damaging chemotherapy. Cur-
rently, 5 PARPis are being investigated in clinical trials.
These include olaparib, rucaparib, niraparib, talazoparib,
and veliparib (Table 1).23 Initially, another agent—
iniparib—was developed as a PARPi. However, after
negative results from a phase 3 trial of iniparib combined
with platinum and gemcitabine chemotherapy for meta-
static TNBC, studies demonstrated that iniparib does
not inhibit PARP in vitro.24,25
PARPis differ in their potency for catalytic inhibi-
tion and their ability to trap PARP. PARP trapping
does not correlate with the potency of PARP enzyme
inhibition. Of the available PARPis, talazoparib is the
most potent catalytic inhibitor (it is approximately 100
times more potent than niraparib).17 Talazoparib is the
most potent in PARP trapping; however, rucaparib,
olaparib, and niraparib also achieve PARP trap-
ping.17,26 Although PARP trapping with veliparib has

2 Cancer Month 00, 2018


TABLE 1. Poly(Adenosine Diphosphate-Ribose)
Polymerase Inhibitors Developed in BRCA-Positive
Breast Cancer in Order of Potency (Lowest to
Highest)
Mechanism
PARP-DNA
Drug Name Inhibition
Veliparib PARP 1/2
Olaparib PARP 1/2/3
Rucapariba PARP 1/2/3
Niraparib PARP 1/2
Talazoparib PARP 1/2
Abbreviation: PARP, poly(adenosine diphosphate-ribose) polymerase.
a
There are data demonstrating higher efficacy of PARP inhibition with ruca-
parib over niraparib.23
been reported, it appears to be the weakest at this
mechanism.26,27 These differences in potency and trap-
ping ability may be predictors of PARPi cytotoxicity in
BRCA-mutant malignancies. Talazoparib reportedly has
the most profound effect, but data are needed to deter-
mine whether this leads to improved clinical out-
comes.28 Increased cytotoxicity from PARP trapping
also may increase toxicities, including cytopenias,
thereby limiting the single agent maximum tolerated
dose and combinations with chemotherapy.27
Single-Agent PARPis in Metastatic Breast
Cancer
The initial phase 1 trial of olaparib enriched with carriers
of BRCA mutations demonstrated promising early results,
in which 47% of patients who had any BRCA-mutant
malignancy achieved a partial response.29 One of the 3
patients with BRCA-mutant breast cancer in that trial had
a complete response lasting more than 60 weeks on ola-
parib 200 mg twice daily. It is noteworthy that no
response was observed in any patients without BRCA
mutations. Several early phase studies with the other
PARPis demonstrated similar signals of efficacy in BRCA-
mutant breast cancer (Table 2).29-47
Multiple phase 2 studies further demonstrated activ-
ity of olaparib in patients who had metastatic breast can-
cer with germline BRCA mutations.30-32 In a phase 2
study, Tutt et al investigated the effects of olaparib mono-
therapy in 54 patients who had centrally confirmed,
germline BRCA-mutant breast cancer. The patients
received olaparib (either 400 mg or 100 mg) twice daily.30
The primary endpoint of overall response rate (ORR) was
22% in the 100 mg cohort and 41% in the 400 mg
cohort.
Cancer Month 00, 2018
PARP Inhibition in BRCA-Mutant Breast CA/Turk and Wisinski
Similarly, phase 2 studies of talazoparib have dem-
onstrated activity in patients with germline BRCA-mutant
breast cancer. The phase 2 ABRAZO trial studied the
use of talazoparib (1 mg daily) in 2 cohorts: 1) patients
with BRCA-mutant, metastatic breast cancer who
Trapping responded to platinum-chemotherapy with disease progres-
sion >8 weeks after the last dose of platinum therapy; and
Complex 2) patients who progressed on at least 3 systemic regimens
No
but had no history of platinum-chemotherapy exposure.38
Yes The ORR was 26% in patients with TNBC and 29% in
Yes those with hormone receptor-positive, HER2-positive or
Yes
Yes HER2-negative disease. It is noteworthy that an increased
time from the last platinum dose in cohort 1 correlated
with improved ORR and progression-free survival (PFS).
Several other ongoing phase 2 and 3 trials are studying
PARPi monotherapy in advanced disease.48-50
The activity of olaparib ultimately was confirmed in
the phase 3 OlympiAD trial, which compared olaparib
versus single agent chemotherapy in metastatic breast can-
cer.33 Patients with HER2-negative, germline BRCA-
mutant breast cancer who had received no more than 2
prior chemotherapy treatments for metastatic cancer were
randomized at a 2:1 ratio to receive either olaparib (300
mg twice daily) or physician’s choice of chemotherapy
(capecitabine, eribulin, or vinorelbine). The primary end-
point of median PFS was significantly longer in the ola-
parib group than in the chemotherapy group (7.0 vs 4.2
months; hazard ratio, 0.58; 95% confidence interval [CI],
0.43-0.80; P < .001). The response rate was nearly 60%
in the olaparib group versus 28.8% in the control arm.
There was no difference in overall survival (OS) between
the olaparib and control arms (19.3 vs 19.6 months,
respectively), likely because of the high degree of cross-
over. In the subgroup analysis, patients with TNBC were
more likely to benefit from olaparib (hazard ratio, 0.43;
95% CI, 0.29-0.63). Conversely, patients with hormone-
receptor positive breast cancers did not benefit statistically
from olaparib (hazard ratio, 0.82; 95% CI, 0.55-1.26).
Of note, patients in OlympiAD who had previously
received platinum chemotherapy (28%) were less likely to
benefit from olaparib therapy (hazard ratio, 0.67; 95%
CI, 0.48-1.14), suggesting an overlap in the mechanisms
of resistance. The rate of grade 3 or greater adverse events
was lower in the olaparib group than in the standard
therapy group (36.6% and 50.5%, respectively). The tox-
icities of olaparib are similar to those of other PARPis, the
most common of which are anemia, nausea/vomiting,
diarrhea, and fatigue. Overall, patient-reported quality-
of-life metrics (the European Organization for Research
and Treatment of Cancer Core 30 Quality-of-Life
3
4
TABLE 2. Poly(Adenosine Diphosphate-Ribose) Polymerase Inhibitors in Metastatic, BRCA-Mutant Breast Cancer

No. of Patients
(No. With
PARP Combination PARP Inhibitor BRCA-Mutated
Inhibitor Agent(s) Reference Phase Tumor Type Dose, mg Breast Cancer) MTD Results
Review Article

Olaparib
NA Fong 200929 1 Solid tumors 10-600 BID 60 (3) 400 mg BID ORR, 33% in BRCA1 breast cancer cohort
NA Tutt 201030 2 BRCA1 breast cancer 400 or 100 BID 54 (54) — ORR, 41% at 400 mg BID, 22% at 100 mg BID
NA Gelmon 201131 2 BRCA1 breast cancer and 400 BID 90 (10) — ORR, 0% in breast cancer cohort
ovarian cancer, TNBC,
HGSOC
NA Kaufman 201532 2 BRCA1 solid tumors 400 BID 317 (62) — ORR, 12.9% in BRCA1 breast cancer cohort
NA Robson 201733 3 BRCA1 breast cancer 300 BID 302 (302) — ORR, 59.9% in olaparib group vs 28.8%;
PFS, 7.0 mo in the olaparib group vs 4.2 mo
Cisplatin Balmana 201434 1 Breast, ovarian, 50-200 BID 53 (17) Not reached ORR, 71% in BRCA1 breast cancer cohort
pancreatic, peritoneal (continuous and (cisplatin 60 mg/m2
cancers intermittent dosing with intermittent
schedules) olaparib 50 mg BID
deemed tolerable)
Carboplatin Lee 201435 1/1b BRCA1 breast and 100-400 BID 45 (8) Not reached ORR, 87.5% in BRCA1 breast cancer cohort
ovarian cancer (continuous and (carboplatin AUC
intermittent dosing 5 with intermittent
schedules) olaparib 400 mg BID
[highest tested dose])
Niraparib NA Sandhu 201336 1 Solid tumors 30-400 qD 100 (4) 300 mg qD ORR, 50% in BRCA1 breast cancer cohort
Talazoparib NA de Bono 201737 1 Solid tumors 0.025-1.10 qD 110 (14) 1.0 mg qD ORR, 50% in BRCA1 breast cancer cohort
NA Turner 201738 2 BRCA1 breast cancer 1.0 qD 84 (84) — ORR: 26% in TNBC cohort; 29% in HR1,
HER21/2 cohort
NA Litton 201739 3 BRCA1 breast cancer 1.0 qD 431 (431) — ORR, 62.6% in talazoparib group vs 27.2%;
PFS 8.6m in talazoparib group vs 5.6m
Rucaparib NA Kristeleit 201740 1/2 Solid tumors 40-500 Daily 56 (27) 600 mg BID ORR 15% in BRCA1 breast cancer cohort
and 240-840 BID
Veliparib NA Puhalla 201441 1 BRCA1 breast and 50-500 BID 98 (13) 400 mg BID ORR 24% in BRCA1 breast cancer cohort
ovarian cancer,
TNBC, HGSOC
Doxorubicin/ Tan 201142 1 Solid tumors 50-150 BID 18 (5) 100 mg BID ORR 60% in BRCA1 breast cancer cohort
cyclophosphamide
43
Carboplatin/ Bell-McGuinn 2013 1 Solid tumors 30-310 BID 62 (4) 250 mg BID ORR, 34% (0% in BRCA1
gemcitabine breast cancer cohort)
Cisplatin/vinorelbine Rodler 201644 1 BRCA1 breast 20-300 BID 50 (14) Not reached (cisplatin ORR, 57% in BRCA1 breast cancer cohort
cancer and TNBC 75 mg/m2 plus
vinorelbine 25 mg /m2
with veliparib 300 mg
[highest tested dose])
Carboplatin Somlo 201745 1/2 BRCA1 breast cancer 50-200 BID 72 (72) 150 mg BID ORR: 14% in BRCA1 cohort, 36% in

Cancer
BRCA2 cohort
Carboplatin/ Pahuja 201546 1 Solid tumors/TNBC 50-200 BID 30 (5) 150 mg BID ORR: 60% in BRCA1 TNBC cohort, 52%
paclitaxel in TNBC cohort
Carboplatin/ Han 201747 2 BRCA1 breast cancer 40 BID 196 (196) — ORR, 77.8% vs 61.3%; PFS, 14.2 vs
paclitaxel 12.3 mo; OS, 28.5 vs 25.0 mo

Abbreviations: 1/2, positive or negative; AUC, area under the curve; BID, twice daily; BRCA, breast and ovarian cancer susceptibility gene; HGSOC, high-grade serous ovarian carcinoma; HR1, hormone recep-
tor positive; MTD, maximum tolerate dose; NA, not applicable/available; ORR, overall response rate; PARP, poly(adenosine diphosphate-ribose) polymerase; TNBC, triple-negative breast cancer.

Month 00, 2018

 PARP Inhibition in BRCA-Mutant Breast CA/Turk and Wisinski
Questionnaire [QLQ-C30]) were improved in the ola-
parib arm, with a mean difference in improvement of 7.5
points (range, 2.5-12.4 points; P 5 .004) compared with
the control arm. Olaparib is now approved by the US
Food and Drug Administration as treatment for patients
who have germline or somatic BRCA1/BRCA2-mutant
breast cancer.
Recently, the activity of talazoparib in BRCA-
mutant breast cancer was demonstrated in the phase 3
EMBRACA trial.39 Initial results from that trial demon-
strated a median PFS of 8.6 months in patients who
received talazoparib compared with 5.6 months in those
who received chemotherapy (P < .0001). In addition, the
ORR in the talazoparib group was more than twice that of
the control arm (62.6% vs 27.2% for chemotherapy; P <
.0001). This benefit from talazoparib was consistent
across subgroups, including hormone receptor status,
BRCA mutation status, prior chemotherapy, and history
of central nervous system metastases.
PARPis in Combination With Chemotherapy in
Metastatic Breast Cancer
It has been demonstrated that PARP inhibition sensitizes
tumor cells to DNA-damaging therapies, including plati-
nums, temozolomide, and radiation.21,22 Given these pre-
clinical data, several clinical trials are studying combination
therapy with the goal of potentiating the effect of cytotoxic
chemotherapy (Table 2).34,35,42-47,51 In particular, veli-
parib has been explored as part of combination therapy. In
a dose escalation study of veliparib plus carboplatin and
paclitaxel in patients with advanced solid tumors, promis-
ing activity was observed, with an ORR of 57% in the
breast cancer cohort. Additional phase 1 data from patients
with breast cancer established the recommended phase 2
dose of veliparib as 150 mg twice daily (on days 22 to 15)
with carboplatin (area under the curve 2) and paclitaxel (80
mg/m2) on days 1, 8, and 15.46 Because of myelosuppres-
sion, this dose is lower than the single agent maximum tol-
erated dose. The subsequent randomized phase 2
BROCADE trial studied the combination of veliparib and
temozolomide or carboplatin/paclitaxel in patients with
platinum-naive, BRCA-mutant, metastatic breast cancer.47
Nearly 78% of patients in that trial who received veliparib
combined with carboplatin/paclitaxel responded to treat-
ment versus an ORR of 61% to the chemotherapy regimen
alone. However, median PFS and OS did not meet the
threshold for a statistically significant improvement. Grade
3 and 4 adverse events occurred in 34.4% and 27.1% of
patients in the veliparib and placebo arms, respectively,
and the most common toxicities were hematologic. Results
Cancer Month 00, 2018
from the veliparib/temozolomide arm of that trial have
not been presented. The international phase 3 BROCADE
trial studying the carboplatin/paclitaxel with or without
veliparib combination is ongoing.
Clinical Development in Early Stage Disease
Given the successful development of PARPis in metastatic
BRCA-mutant breast cancer, trials are underway to study
their role in early stage disease in both the neoadjuvant
and adjuvant settings. The I-SPY 2 trial is a multicenter,
randomized phase 2 platform with multiple experimental
arms adding novel agents or combinations to standard
neoadjuvant chemotherapy with a primary endpoint of
pathologic complete response (pCR).52 Patients with
TNBC were randomized to receive veliparib (50 mg twice
daily on days 1-21) with carboplatin and paclitaxel versus
paclitaxel alone for 4 cycles. All patients then received 4
cycles of doxorubicin and cyclophosphamide (AC) fol-
lowed by primary breast surgery. An estimated pCR rate
of 52% (95% CI, 36%-66%) was observed in the investi-
gational veliparib/carboplatin arm versus 26% (95% CI,
9%-43%) in the standard treatment arm (paclitaxel fol-
lowed by AC). The use of pCR as the primary endpoint
has been associated with improved event-free survival in
breast cancer.53 It is notable that results based on germline
BRCA mutation status have not been reported for this
cohort. This promising activity is the basis for the phase 3
Brightness Study, which randomized patients with stage
II and III TNBC to add carboplatin plus veliparib, carbo-
platin alone, or placebo to standard neoadjuvant paclitaxel
chemotherapy followed by AC.54 This study demon-
strated an improved pCR in patients who received pacli-
taxel, carboplatin, and veliparib compared to paclitaxel
(53% vs 31%, P < .0001). However, the addition of veli-
parib to carboplatin and paclitaxel did not improve pCR
(58%, P 5 .36) compared to carboplatin and paclitaxel
alone. Additionally, patients with BRCA-mutant breast
cancer did not benefit from the addition of veliparib with
carboplatin and paclitaxel. Of note this cohort only repre-
sented 15% of the study population and thus was not ade-
quately powered to analyze this subgroup.
Neoadjuvant talazoparib monotherapy has demon-
strated promising activity in a pilot phase 2 study. Thir-
teen patients who had BRCA-mutant breast cancer
received 2 months of talazoparib monotherapy, which
resulted in 88% (range 30%-98%) median tumor shrink-
age by ultrasound.55 The study was halted early to allow
for the expansion of neoadjuvant talazoparib as the only
treatment before surgery to assess for the pCR rate.56
5
Review Article
The phase 3 OlympiA study will assess the safety
and efficacy of up to 12 months of adjuvant olaparib
(300 mg twice daily) versus placebo in patients with
BRCA-mutant TNBC or hormone receptor-positive/
HER2-negative breast cancer.57 Patients must have com-
pleted definitive local treatment and neoadjuvant/adju-
vant chemotherapy. Randomization will be stratified by
hormone receptor status, prior neoadjuvant versus adju-
vant chemotherapy, and prior receipt of platinum chemo-
therapy. The post-neoadjuvant treatment group will
include patients who did not achieve pCR. The primary
endpoint is invasive disease-free survival with secondary
endpoints of OS, distant disease-free survival, and the
development of new primary malignancies as well as safety
and tolerability. Olaparib is also being studied in the neo-
adjuvant setting in combination with platinum-based che-
motherapy for basal TNBC and BRCA-mutant breast
cancer.58
Finally, rucaparib is being tested in a phase 2 trial as
adjuvant treatment with cisplatin in patients who have
TNBC and BRCA-mutant breast cancer with residual dis-
ease after receiving anthracycline and/or taxane neoadju-
vant therapy.59 Patients were randomized to cisplatin with
or without rucaparib for 24 weeks. Preliminary data dem-
onstrated a significant improvement in 2-year disease-free
survival with rucaparib and cisplatin (69.9% vs 55.9%,
respectively; P 5 .04) in patients who received an
anthracycline-containing regimen. It is noteworthy that
BRCA mutation status did not impact disease-free survival.
RESISTANCE TO PARP INHIBITION
Like other targeted therapies, malignancies can acquire
resistance to PARPi therapy. One proposed mechanism is
restoration of the HR-repair pathway. There is evidence
that the increased genomic instability promoted by PARP
inhibition can lead to reversion mutations, leading to resto-
ration of BRCA1/BRCA2 function and PARP resistance.60
Other mechanisms of HR-repair restoration include loss of
DNA-repair proteins p53 binding protein 1 (53BP1) and
REV7.61,62 A second mechanism of resistance is increased
drug efflux, leading to a reduction in PARPi intracellular
concentration through the up-regulation of P-glycoprotein
expression.29 Finally, changes in PARP1 expression levels
in cancer cells also lead to resistance to PARPis. Elevation
of PARP1 mediates resistance to PARPis and is related to
worse outcomes in patients with breast cancer.63,64 Some
of these resistance mechanisms are shared between PARPis
and platinum chemotherapy, although the degree of
overlap is not clear.65 The resistance mechanisms in
platinum-resistant disease may limit the clinical utility of
6 Cancer
PARPis after platinum chemotherapy, and additional strat-
egies to overcome acquired resistance will be needed. Nota-
bly, most ongoing studies of PARPis exclude patients who
have platinum-resistant disease.
EXPANDING CLINICAL APPLICATION FOR
PARP INHIBITORS
The antitumor activity observed with PARPis in BRCA-
mutant breast and ovarian cancers has demonstrated syn-
thetic lethality as a therapeutic strategy. There are emerg-
ing data on the efficacy of PARPis in other BRCA-mutant
malignancies, including prostate and pancreatic cancers.32
It remains to be determined whether this can be expanded
into other tumor types with deficiencies in DNA-repair
mechanisms without BRCA1/BRCA2 germline mutations.
Investigation has expanded in malignancies with the
“BRCAness” phenotype. The term “BRCAness” refers to
malignancies that have not arisen from germline BRCA1
or BRCA2 mutations but nonetheless share the phenotypic
and molecular features of HR-repair deficiency because of
a different genetic signature.66 This includes somatic
mutation in either BRCA1 or BRCA2, promoter hyperme-
thylation of BRCA1, or mutations in other genes involved
in double-stranded break DNA repair (ataxia-telangiecta-
sia mutated [ATM], RAD51, PALB2, Fanconi anemia
complementation group [FANC], phosphatase and tensin
homolog [PTEN]).66 These malignancies share the same
therapeutic vulnerabilities with BRCA-associated tumors,
including sensitivity to platinum chemotherapy.67,68
There is no standardized biomarker of “BRCAness”
currently available. Significant effort has been made to
develop classifiers of “BRCAness” to help predict suscepti-
bility to PARP inhibition.68-71 Recently, Severson et al
developed a 77-gene signature to help define “BRCAness”
and to investigate its ability to predict response to veliparib
and carboplatin neoadjuvant therapy within the I-SPY2
clinical trial.72 Although the trial was limited by a small
sample size, the authors demonstrated an association
between the “BRCAness” classification and patient
response observed in the verliparib/carboplatin arm. Stud-
ies also are evaluating a HR deficiency score to help identify
“BRCAness” by summing 3 different measures of genomic
instability (loss of heterozygosity, telomeric allelic imbal-
ance, and large-scale state transitions).73 A positive score,
defined as >42, was able to identify patients who were
more responsive to platinum chemotherapy. There are
ongoing studies expanding on this hypothesis with other
PARPis, including rucaparib and talazoparib.49,74
Other strategies to extend the role of PARP inhibition
in BRCA-mutant breast cancer include phosphoinositide
Month 00, 2018
 PARP Inhibition in BRCA-Mutant Breast CA/Turk and Wisinski
3-kinase (PI3K) inhibition. In addition to its role in propro-
liferative and antiapoptotic functions, the PI3K/MAPK
pathway contributes to the repair of double-stranded DNA
breaks in tumor cells.75 In preclinical breast cancer models,
the combination of a PI3K inhibitor and olaparib delayed
tumor growth in mouse models, suggesting that combined
inhibition of both PI3K and PARP might be effective treat-
ment for BRCA-mutant malignancies.75 Preliminary clinical
efficacy has been demonstrated by Matulonis et al, who
studied a combination of olaparib with the PI3K inhibitor
BKM120 in patients with ovarian cancer or TNBC and
reported an ORR of 24% (10 of 42 patients).76
Finally, combinations of PARPis with immunothera-
pies, including antibodies to cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) and programmed death 1/
programmed death-ligand 1 (PD1/PD-L1) are being clini-
cally investigated. Tumors with HR deficiency have higher
genomic instability, and this may be associated with an ele-
vated neoantigen load, which, in turn, has been associated
with a stronger antitumor immune response.77,78 This
combination rationale is also supported by preclinical evi-
dence that immune therapy may be enhanced with
PARPis.79 In addition, there is evidence that tumors with
DNA-repair deficiency may induce a stimulator of inter-
feron genes (STING)-dependent, innate immune response
in a cell cycle-specific manner.80 In an early phase 1 trial,
Lee et al studied the combination of durvalumab with ola-
parib or an antiangiogenesis agent cediranib in advanced
female solid malignancies.81 Among 12 evaluable patients
who received durvalumab and olaparib, 2 had a partial
response, and 8 had stable disease for >4 months, yielding
a disease control rate of 83%. On the basis of this emerging
evidence, there are ongoing trials studying the combination
of PARPis with PD-L1 inhibitors.82,83
CONCLUSIONS
PARP inhibition is an emerging strategy for the treatment
of BRCA-mutant breast cancer. With the recent Olym-
piAD data, PARPis have been identified as an agent for
consideration in patients who have metastatic disease.
PARPis should be considered in particular for women
who have BRCA-mutant TNBC based on the improved
outcomes and lack of other targeted therapy options.
Future directions will include optimizing combination
therapy with chemotherapy, other targeted therapies, and
immunotherapies, understanding and overcoming resis-
tance mechanisms, and expanding the application of
PARPis beyond BRCA-mutant breast cancer, particularly
in malignancies with “BRCAness.”
Cancer Month 00, 2018
FUNDING SUPPORT
This work was supported by a Cancer Center Support Grant from
the National Cancer Institute (P30 CA014520).
CONFLICT OF INTEREST DISCLOSURES
Kari B. Wisinski served on the AstraZeneca and Pfizer advisory
boards outside the submitted work. Anita A. Turk made no
disclosures.
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