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Yadav, D. Role of PARP in TNBC. Encyclopedia. Available online: https://encyclopedia.pub/entry/15374 (accessed on 14 June 2024).
Yadav D. Role of PARP in TNBC. Encyclopedia. Available at: https://encyclopedia.pub/entry/15374. Accessed June 14, 2024.
Yadav, Dharmendra. "Role of PARP in TNBC" Encyclopedia, https://encyclopedia.pub/entry/15374 (accessed June 14, 2024).
Yadav, D. (2021, October 25). Role of PARP in TNBC. In Encyclopedia. https://encyclopedia.pub/entry/15374
Yadav, Dharmendra. "Role of PARP in TNBC." Encyclopedia. Web. 25 October, 2021.
Role of PARP in TNBC
Edit

Triple-negative breast cancer is a combative cancer type with a highly inflated histological grade that leads to poor theragnostic value. Gene, protein, and receptor-specific targets have shown effective clinical outcomes in patients with TNBC. Cells are frequently exposed to DNA-damaging agents. DNA damage is repaired by multiple pathways; accumulations of mutations occur due to damage to one or more pathways and lead to alterations in normal cellular mechanisms, which lead to development of tumors. Advances in target-specific cancer therapies have shown significant momentum; most treatment options cause off-target toxicity and side effects on healthy tissues. PARP (poly(ADP-ribose) polymerase) is a major protein and is involved in DNA repair pathways, base excision repair (BER) mechanisms, homologous recombination (HR), and nonhomologous end-joining (NEJ) deficiency-based repair mechanisms. DNA damage repair deficits cause an increased risk of tumor formation. Inhibitors of PARP favorably kill cancer cells in BRCA-mutations. For a few years, PARPi has shown promising activity as a chemotherapeutic agent in BRCA1- or BRCA2-associated breast cancers, and in combination with chemotherapy in triple-negative breast cancer.

breast cancer PARP (poly(ADP-ribose) polymerase) TNBC therapeutic target DNA damage repair signaling pathway

1. Introduction

Breast cancer (BC) is the most common cancer that occurs in women worldwide [1]. BC is caused by accumulation of somatic mutations in breast cells, which impair cell division and DNA repair mechanisms, resulting in irregular cell growth proliferation, differentiation, and ultimately, progression of tumorigenesis [2][3]. Triple-negative breast cancer is more belligerent and has a poorer prognosis than other types of breast cancer. Triple-negative breast cancer (TNBC) accounts for approximately 15% of all BC, and lacks human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) expression and amplification. If we compare it with another type of BC, TNBC exhibits inherently aggressive clinical symptoms and poorer clinical outcomes [4][5][6][7]. Presently, the clinical targeted drugs for BC include poly-(ADP)-ribose polymerase (PARP) inhibitors (PARPi), CDK4/6 inhibitors (CDK4/6i), PI3K inhibitors, and AKT inhibitors—but none of these drugs alone are very effective against TNBC [8]. There is an urgent need for the rational exploration of drug compatibility and potential targets for TNBC [7][8]. PARP1 (poly (ADP-ribose) polymerase 1) was discovered approximately 50 years ago and is involved in gene transcription, DNA repair, and cell death [9]. PARP1 has acceptable therapeutic importance against cancer, as shown in Figure 1 and Figure 2 [10]. PARP inhibitors have emerged as effective treatments in clinical trials for sporadic TNBC and BRCA-associated cancers [11]. There are various types of PARP inhibitors under clinical trial such as olaparib, BSI-201, talazoparib, rucaparib veliparib, and niraparib [10][11]. Inhibition of the PARP-1 and PARP-2 enzymes is believed to be attained mainly via binding of the NAD+ catalytic domain side chain, extending out of the NAD catalytic site of the PARP inhibitor [12]. It also thought that the PARP enzyme locks on to the site of DNA damage, preventing its usual release from DNA molecules [10][11][12][13][14][15]. PARP-1 binds to the damaged site through its zinc-finger domains in the presence of SS (single-stranded)-DNA breaks [13]. PARP-1 and poly (ADP) polymerization recruits and binds other DNA-repair proteins, leading under normal cell physiology to an increasingly negative charge on the enzyme, and eventual dissociation from the DNA [14]. Some clinical investigations have shown the need for HRD (homologous recombination DNA repair) in facilitating PARP inhibition, via loss of BRCA function [16][17]. Researchers from the field have suggested that PARP inhibition is associated with the induction of DNA damage by chemotherapy in the more general cohort of TNBC.
Figure 1. Role of PARP inhibitors in treatments for BRCA mutant breast cancer.
Figure 2. Schematic delineating the multifaceted nature of poly (ADP) ribose polymerase (PARP): DNA repair, chromatin modification, inflammation, transcriptional regulation, and cell death. Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts as a co-activator of NFkB signaling, which can propagate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively clustered DNA lesions (OCDLs). The formation of OCDLs is elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.

2. Clinical Applications of PARP Inhibitors in TNBC

PARP inhibitors have been shown to have effective clinical outcomes against different types of cancer. There are various clinical trials registered investigating PARPi therapies (Table 1Table 2 and Table 3).
Table 1. List of PARP inhibitors.
Compound Name Compound Structure Efficacy IC50
Nicotinamide Biomedicines 09 01512 i001 PARP inhibitor and by-product of the PARP reaction; many pharmacological actions other than that of inhibiting PARP 210 μM
3-aminobenzamide Biomedicines 09 01512 i002 Benzamides are free radical scavengers, among other
pharmacological actions
33 μM
PD128763 Biomedicines 09 01512 i003 Cytoprotective agent, chemosensitizer, and radiosensitizer; adverse effect of compound causes hypothermia 420 nM
DPQ Biomedicines 09 01512 i004 A commonly used Warner–Lambert PARP inhibitor compound based
on an isoquinoline core
1 μM
NU1025 Biomedicines 09 01512 i005 Potentiators of anticancer
agent cytotoxicity
400 nM
4-ANI Biomedicines 09 01512 i006 PARP in DNA repair and cell death 180 nM
ISO Biomedicines 09 01512 i007 PARP in DNA repair and cell death 390 nM
Olaparib
(Lynparza)
Biomedicines 09 01512 i008 Use in a BRCA1-positive patient with metastatic triple-negative breast cancer, without the initial use of platinum-based chemotherapy, showed significant rapid near-resolution of large liver metastasis while patient experienced gout-like symptoms 1 nM
Niraparib (Zejula) Biomedicines 09 01512 i009 Niraparib in combination with pembrolizumab in patients with triple-negative breast cancer 4 nM
Talazoparib
(Talzenna)
Biomedicines 09 01512 i010 Ferm line BRCA-mutant, HER2-negative locally advanced or metastatic breast cancer 0.6 nM
Veliparib (ABT-888) Biomedicines 09 01512 i011 Received orphan drug status
for lung cancer
2 nM
INO-1001 Biomedicines 09 01512 i012 Potent enhancer of radiation sensitivity and enhances radiation-induced cell killing by interfering with DNA repair mechanisms, resulting in necrotic cell death 105 nM
E7449 Biomedicines 09 01512 i013 Antitumor activity of E7449; a novel PARP 1/2 and tankyrase 1/2 inhibitor 1 nM
CEP-8983 Biomedicines 09 01512 i014 Increases the sensitivity of chemoresistant tumor cells to temozolomide 20 nM
Pamiparib
(BGB-290)
Biomedicines 09 01512 i015 Pamiparib has potent PARP trapping, the capability to penetrate the brain, and can be used for the research of various cancers including solid tumors 0.9 nM
Fluzoparib
(SHR-3162)
Biomedicines 09 01512 i016 Inhibitor of poly-adenosine diphosphate(ADP)ribose polymerase (PARP) 1/2 being developed for the treatment of BRCA1/2-mutant solid tumors. 1.5 nM
Table 2. Efficacy of PARP inhibitors.
Name of the Molecules Tmax (h) t (h) AUC (lgh/ mL) Cmax (lg/mL) CL/F (L/h) Vz/F References
Olaparib capsule formulation 300 mg 1.49
(0.57–3.05)
13.02 (8.23) 55.20 (67.4) 8.05 (24.3) 6.36 (3.47) 112.1 (59.84) [18]
Olaparib tablet formulation 300 mg single dose (fasted) 1.50
(0.50–5.85)
12.2
(5.31)
43.6 (54.3) [AUCt]
43.0 (55.2)
[AUC]
7.00 (35.0) 7.95 (4.23) 146 (142) [19]
Olaparib tablet formulation 300 mg single dose (fed) 4.00
(1.00–12.0)
12.2
(5.31)
46.0 (56.6) [AUCt]
45.4 (57.1)
[AUC]
5.48 (40.5) 7.55 (3.99) 127 (107) [19]
Veliparib monotherapy 40 mg (10 mg, fasting) 1.2 ± 0.8 5.9 ± 1.3 2.23 ± 0.82 [AUCt]
2.43 ± 1.07
[AUC]
0.36 ± 0.13 19.0 ± 7.36 NA [20][21]
Veliparib monotherapy 40 mg (10 mg, fed) 1.2 ± 0.7 5.8 ± 1.2 2.45 ± 0.93 [AUCt]
2.65 ± 1.17
[AUCt]
0.37 ± 0.12 17.3 ± 6.41 NA
Veliparib monotherapy 40 mg (40 mg, fasting) 1.3 ± 0.9 5.8 ± 1.3 2.24 ± 0.98 [AUCt]
2.45 ± 1.24
[AUCt]
0.34 ± 0.12 19.5 ± 7.66 NA
Veliparib monotherapy 40 mg (40 mg, fed) 2.5 ± 1.1 5.8 ± 1.4 2.14 ± 0.80 [AUCt]
2.35 ± 1.06
[AUCt]
0.28 ± 0.09 19.7 ± 7.51 NA
Veliparib metabolite M8 2.4 (3.5–9.8) 0.3–1.9
[AUCint]
0.011
(0.007–0.014)
NA NA [20][21]
Niraparib 300 mg/day 3.1 (2.0–6.1) a 14.117
(AUC24)b
1.921 NA NA [12]
Niraparib metabolite: unlabeled M1 plasma 9.02 78.4 41.2 (AUCt) 476 NA NA [15]
Table 3. Clinical Trials of PARP Inhibitors in TNBC.
Name of Drug Types of Inhibitors Prior Treatment Type of Population Status ClinicalTrials.gov
Identifier
AZD1775
in patent with TNBC LYNPARZATM
PARP
Inhibitor,
patent with TNBC
Olaparib in combination with AZD6738 mutated (ATM) Inhibitor of
Ataxia-Telangiectasia and WEE1 inhibitor
Phase II NCT03330847
AZD1775
in patent with TNBC LYNPARZATM
PARP
Inhibitor,
patent with TNBC
Olaparib with radiation therapy, after
chemotherapy
Inhibitor of
ataxia-telangiectasia
Phase I NCT03109080
AZD1775,
LYNPARZATM
Patent with TNBC Olaparib with atezolizumab Inhibitor of
PD-L1
Phase II NCT02849496
AZD1775,
LYNPARZATM
Patent with TNBC Oolaparib with paclitaxel and
carboplatin
Inhibitor of
germline BRCA mutated
Phase II/III NCT03150576,
NCT02789332
AZD1775,
LYNPARZATM
Patent with TNBC Olaparib with
AZD2171 orally
Inhibitor of VEGFR tyrosine kinase Phase I/II NCT01116648
AZD1775,
LYNPARZATM
Patent with TNBC Olaparib with PI3K inhibitor, BKM120 Inhibitor of BKM120 Phase I NCT01623349
AZD1775,
LYNPARZATM
Patent with TNBC Olaparib with onalespib Inhibitor of heat shock protein 90 Phase I NCT02898207
AZD1775,
LYNPARZATM
Patent with TNBC Olaparib with
AZD2014
mTORC1/2 or
Oral AKT inhibitor
Phase I/II NCT02208375
PARP1/2 inhibitor
Veliparib
Patent with TNBC Veliparib in combination
with cyclophosphamide
Inhibitor of EGFRHER2BRCA, and tyrosine
kinase
Phase II and failed in phase
III trials
NCT01306032
PARP1/2 inhibitor
Veliparib
Inhibitor of
tyrosine
kinase, HER2, and BRCA
Veliparib in combination
with carboplatin
Patients with TNBC Completed phase I study NCT01251874
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRBRCA, and tyrosine
kinase
Veliparib with
vinorelbine
Patients with TNBC Completed phase I NCT01281150
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib with cisplatin Patients with TNBC Completed phase I NCT01104259
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib with pegylation Patients with TNBC Completed phase I NCT01145430
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib with pegylation Patients with TNBC Completed phase I NCT01145430
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib with lapatinib Patients with TNBC Phase I NCT02158507
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib in combination with irinotecan HCl Patients with TNBC Phase I I NCT00576654
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib with
cisplatin
Patients with TNBC Phase II NCT02595905
AZD2281 and
Ku-0059436 PARP1/2 inhibitor
(Selective)
PARP inhibitor; BRCA
Mutated
Olaparib alone, or in combination with durvalumab MEDI4736 against
PD-L1
HER2-negative
treated mTNBC
Phase-II NCT00679783
NCT03544125
NCT02484404
NCT03167619
NCT02681562
NCT02484404
PARP1/2 inhibitor
Veliparib
Inhibitor of EGFRHER2BRCA, and
tyrosine
kinase
Veliparib plus carboplatin Patients with TNBC Phase III NCT02032277
Iniparib BSI-201 and SAR240550 Competitive PARP inhibitor; ability to form adducts with many cysteine-containing proteins Combination with
gemcitabine and carboplatin
Patients with TNBC Phase II NCT00813956
NCT01045304
NCT01130259
Iniparib BSI-201 and SAR240550 Competitive PARP inhibitor; ability to form adducts with many cysteine-containing proteins Combination of iniparib
with paclitaxel for TNBC compared
to paclitaxel alone
Patients with TNBC Competed phase II NCT01204125
Iniparib BSI-201 and SAR240550 Competitive PARP inhibitor; ability to form adducts with many cysteine-containing proteins Iniparib with irinotecan Patients with TNBC Phase II trial NCT01173497
Niraparib ≥1 anti-HER2 treatment;
PARP inhibitor
Niraparib
plus
trastuzumab IV
Metastatic HER2+ breast
cancer
Phase Ib/II (recruiting) NCT03368729
Niraparib PARP inhibitor One anthracycline and/or
taxane in the (neo-) adjuvant
or Niraparib
Advanced/metastatic BRCA1-
like
Phase-II, Active, not recruiting NCT02826512
Niraparib PARP inhibitor ≥1 line of therapy Niraparib
plus everolimus
Patients with TNBC Phase I Recruiting NCT03154281
Niraparib Germline
BRCA mutation-positive
(PARP inhibitors)
≤2 prior cytotoxic regimens and
Niraparib
versus
physician‘s choice
Advanced or metastatic
breast cancer
Phase III Active, not yet
recruiting
NCT01905592
(BRAVO)
Niraparib Metastatic
TNBC inhibitors
(PARP inhibitors)
≤2 lines of cytotoxic therapy,
Niraparib
plus
pembrolizumab
Advanced or metastatic
TNBC
Phase I/II Active, not yet
recruiting
NCT02657889
(KEYNOTE-162)
veliparib Metastatic
TNBC inhibitors
(PARP inhibitors)
≤2 lines of cytotoxic
Chemotherapy, Carboplatin, and paclitaxel
with or without veliparib
Locally advanced
unresectable BRCA associated
Phase III Recruiting NCT02163694
veliparib Metastatic
TNBC inhibitors
(PARP inhibitors)
Veliparib with temozolomide
versus veliparib with
carboplatin and paclitaxel
versus placebo with
carboplatin and paclitaxel
≤2 lines of cytotoxic
chemotherapy
Metastatic
TNBC
Randomized
phase II, Ongoing
NCT01506609
veliparib Metastatic
TNBC inhibitors
(PARP inhibitors)
Veliparib versus
atezolizumab versus
veliparib plus atezolizumab
Stage III–IV TNBC Randomized
phase II Ongoing
NCT02849496
veliparib Metastatic
TNBC inhibitors
PARP inhibitors)
Cisplatin and placebo
versus cisplatin and
veliparib
≤1 line of cytotoxic
chemotherapy for
metastatic disease
Metastatic TNBC and/or
BRCA mutation-associated
breast cancer
Phase II Active, not recruiting NCT02595905
veliparib Metastatic
TNBC inhibitors
PARP inhibitors)
Temozolomide and veliparib
≥1 chemotherapy
regimen
Metastatic TNBC and/or
BRCA mutation-associated
breast cancer
Phase II, Active, not recruiting NCT01009788
Talazoparib Neoadjuvant therapy None Primary breast cancer ≥1
cm with a deleterious
BRCA mutation
Phase II, Active, not recruiting NCT02282345
Talazoparib Advanced TNBC and HR
deficiency and advanced
HER2-negative breast cancer or other solid
tumors with a
mutation in HR pathway
genes
≥1 line of therapy Talazoparib Phase II, Recruiting NCT02401347
Talazoparib Metastatic
TNBC inhibitors
PARP inhibitors
Platinum-containing regimen
with disease progression > 8
weeks
Metastatic breast cancer
with BRCA mutation
Phase II Terminated (Primary Analysis and study completed Not stopped NCT02034916
(ABRAZO)
Talazoparib Metastatic
TNBC inhibitors
PARP inhibitors
≤3 chemotherapy-inclusive
regimens Talazoparib
versus physician‘s
choice
Locally advanced and/or
metastatic breast cancer
with germline BRCA
mutations
Phase III Completed NCT01945775
(EMBRACA)
Rucaparib Metastatic
TNBC inhibitors
PARP inhibitors
≤5 prior chemotherapy Rucaparib
regimens in the last 5 years
Patients presenting with metastatic breast cancer (MBC) Phase II, Completed NCT00664781
Rucaparib Metastatic
TNBC inhibitors
PARP inhibitors
≥1 line of chemotherapy, Rucaparib Patients with a BRCAness
genomic signature
Phase II Completed NCT02505048
(RUBY)
Rucaparib Stage I–III patients with
TNBC or inhibitors
PARP inhibitors
Neoadjuvant chemotherapy Cisplatin with rucaparib ER/PR+, HER2-
negative breast cancer with known BRCA1/2 mutations
Phase II Completed NCT01074970
Rucaparib TNBC inhibitors ≥3 prior chemotherapy
regimens, Rucaparib
Patients with advanced solid tumors with evidence of
germline
Phase I/II Active, not
recruiting
NCT01482715
Rucaparib TNBC inhibitors ≤5 prior chemotherapy
regimens in the last 5 years, Rucaparib
Patients with MBC carriers of a BRCA1/2 Phase II Completed NCT00664781
Rucaparib TNBC inhibitors ≥1 line of chemotherapy Rucaparib Patients with a BRCAness
genomic signature
Phase II Completed NCT02505048
(RUBY)
Rucaparib TNBC inhibitors Neoadjuvant chemotherapy Cisplatin with
rucaparib
Advanced solid
tumors with evidence of
germline or somatic BRCA mutation
Completed NCT01074970
Rucaparib TNBC inhibitors ≥3 prior chemotherapy
regimens
Advanced solid
tumors with evidence of
germline or somatic BRCA mutation
Phase I/II Active, not
recruiting
NCT01482715

2.1. Olaparib

Olaparib is a potent oral PARP inhibitor effective against BRCA1 and BRCA2 mutations [22]. A multicentric clinical evaluation of olaparib was carried out using it as a monotherapy for inpatients with germline BRCA1/2 mutations [23][24][25]. Olaparib was administered to the patient twice a day at a dose of 400 mg. The clinical trial was performed with 298 patients, out of which, effective clinical therapy was observed in 12.9%, with adverse effects of vomiting, nausea, and fatigue observed [26][27][28][29][30]. Another study was performed to optimize the drug concentration and determine its maximum dose and minimum dose. In patients with BRCA1 and BRCA2 mutations, an ORR (overall response rate) of 11 (41%) was observed in 27 patients with a 400 mg dose twice daily. An ORR of 6 (22%) was observed in 27 patients with 100 mg doses twice daily; the ORR was observed to be 7/13 (54%) with higher doses and 4/16 (25%) with lower doses in TNBC patients. In higher dose-tested patients, some adverse effects were observed, such as anemia, vomiting, nausea, and fatigue. Olaparib was approved by the FDA based on the clinical outcomes of the patient [27][28][29][30]. A phase 3 clinical trial employed olaparib monotherapy in germline BRCA mutations with HER2 negativity and, at minimum, previous chemotherapy therapy [29]. A total of 300 patients were selected randomly in a 2:1 ratio into two groups; group one was administered 300 mg olaparib twice daily, and 92 patients in group two were administered vinorelbine or capecitabine and eribulin in 21-day cycles. Out of 300, 49.8% of the TNBC patients were included in the olaparib group and 49.5% of the TNBC patients received standard therapy [3][26][27][28]. Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% CI, 0.43 to 0.80; p < 0.001). In the subgroup analysis, the hazard ratio for PFS was 0.43 (95% CI, 0.29–0.63) for patients with TNBC [3][28][29][30]. The response rate was 59.9% in the olaparib group and 28.8% in the standard therapy group, while the rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard therapy group; the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively [28][29][30][31]. Metabolism of olaparib occurs via oxidation and dehydrogenation and does so progressively via the use of other factors such as sulfate conjugate and glucuronide [27][28]. Olaparib is mainly excreted through urine (44%) and feces (42%) [28].
OlympiAD was a randomized open clinical phase III trial (NCT02000622) assessing the daily administration of 600 mg olaparib tablets. A total of 302 patients who had received two or fewer prior treatments were randomized in a 2:1 ratio to olaparib or chemotherapy. The results showed significantly prolonged PFS with olaparib versus standard therapy (7.0 vs. 4.2 months; hazard ratio (HR), 0.58; 95% CI, 0.43–0.8; p < 0.001); Response rates were observed to be 59.9% vs. 28.8% (olaparib vs. standard group) [26]. Olaparib was the first PARP inhibitor to establish higher efficacy and tolerability than standard chemotherapy in gBRCA-mutated advanced BC [27][28][29][30]. According to earlier results, the FDA approved olaparib as the first PARP inhibitor for the treatment of this patient subgroup. However, in the interim analysis, no differences in overall survival (OS) were observed between the two groups [30][31][32]. The 3-year OS was 40.8% versus 12.8% in the two groups, respectively, in patients with TNBC. Currently, research on PARP inhibitors for adjuvant therapy and neoadjuvant therapy, as well as for the prevention of BC, is ongoing—including the OlympiA (phase III) and GeparSixto studies; in the future, the results of these studies will evaluate adjuvant therapy with olaparib for HER-2-/gBRCAm BC and explore the value of a PARP inhibitor in neoadjuvant therapy, respectively [33][34][35]. Various remarkable drugs have been approved to benefit patients with TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation-associated breast cancer (gBRCAm-BC) and immunotherapy using the checkpoint inhibitor atezolizumab, in combination with nab-paclitaxel for programmed cell death-ligand 1-positive (PD-L1+) advanced TNBC [28][35].

2.2. Iniparib (BSI-201)

Iniparib was the first potent PARP1 inhibitor, effective against cancer cell lines with 40–128 μM IC50 values, and is not toxic at 200 mg/kg in Syrian hamsters [36][37]. The efficacy of iniparib (BSI-201) was established by caspase-3 and TUNEL staining of OVCAR-3 tumors; iniparib efficacy was high in combination with topotecan [32][33][34]. Iniparib used together with a PARP-1 inhibitor has also shown efficacy in DNA repair mechanisms [34]. One clinical trial investigated patients with metastatic TNBC [36][37], in which a total of 123 patients were selected randomly and two groups were made; in each group, patients received 1000 mg/m2 gemcitabine and carboplatin on days 1 and 8, either with or without 5.6 mg/kg iniparib on days 1, 4, 8, and 11, over a cycle of 21 days [36][38]. The clinical efficacy of iniparib was increased with carboplatin and gemcitabine, and the ORR was increased from 32% to 52%. The time duration of the iniparib dose was also increased from a median PFS of 3.6 months to 5.9 months, and the median ORR from 7.7 months to 12.3 months; the hazard ratio for death was observed to be 0.57; p = 0.01. ORR and PFS were analyzed further in a phase III clinical trial; the trial did not find successful treatment of patients [38].

2.3. Niraparib

Niraparib is a PARP1 and PARP1 inhibitor. Niraparib is indicated as a maintenance treatment for recurrent cancer patients, mainly with HR deficiency (HRD) with positive status [35][39]. HRD has been linked to deleterious BRCA mutations in patients, with disease development occurring more than six months later following platinum-based chemotherapy [35][39]. Niraparib was extended for use in the care treatment of adults following first-line platinum-based chemotherapy [29][35].
Patients with solid tumors (BRCA1 or BRCA2 mutation carrier) were enrolled in a phase I clinical trial [38][39][40][41]. The currently used therapeutic option was tested along with niraparib in BRCA-mutated metastatic breast cancer; patients with germline BRCA mutations were treated with a PARP inhibitor rather than chemotherapy, and the availability of PARP inhibitors increased [38][39][40][41]. No safety concerns have been noted by the IDMC (Independent Data Monitoring Committee) concerning niraparib [38][39][40][41]. The clinical outcome from the BRAVO (Breast Cancer Risk and Various Outcomes) trial is expected to be supportive of a planned trial of niraparib in combination with an anti-PD-1 antibody in women with metastatic TNBC [38][39][40][41].

2.4. Veliparib (ABT-888)

Veliparib (ABT-888) is a potent PARP1 and PARP2 inhibitor used as a neoadjuvant. It has good pharmacokinetic properties and has shown effective clinical outcomes [42]. Veliparib is effective in platinum-based therapy in xenograft models [42][43]. Significantly, the eradication of solid tumors following neoadjuvant chemotherapy, designated the clinical–pathological response in breast and axillary nodes during surgery, is connected with progression-free survival (PFS) and overall survival rates (OSRs)—with strong correlations in TNBC and HER2-positive disease, raising interest in the neoadjuvant approach [44][45]. Veliparib was clinically evaluated in TNBC patients in combination with carboplatin; it was also tested against the NAD+ catalytic enzyme SIRT2, showing inactivity against >5000 nM of the enzyme. Receptor-binding assays were performed in 74 patients for Veliparib receptor profile analysis at a concentration of 10 μM [43][44][45]. Multiple investigations were carried out, such as control-specific binding at 50% of human 5-HT7 (84%) sites with an IC50s value of 1.2 μM; IC50s at H1(61%), with an IC value of 5.3 μM; and human 5-HT1A (91%) with a IC50s value of 1.5 μM. c-Met knockdown cells show shMet-A (95% CI = 4–4.5) tumor growth retardation with up to 60 μM Veliparib (ABT-888) [43][44][45]. When treated with 38 μM Veliparib, c-Met knockdown cells show shMet-B (95% CI = 1.3–2.5) tumor growth inhibition. Cell viability was higher with 1,000 µM sulfur mustard (SM) exposure in HaCaT cells at 6 h post-treatment by Veliparib [43][44][45]. Additionally, Veliparib no longer shows protective effects at 24 h post SM exposure.
Randomized patients were selected to receive either paclitaxel as monotherapy or veliparib and carboplatin as a combination therapy, followed by doxorubicin and cyclophosphamide given in four cycles [45]. Clinical outcomes were examined, with estimated rates of PCR of 51% in the combination group with TNBC patients and 26% in the control group of patients [45]. For the phase III clinical trial, 634 patients were selected based on histological clinical stage II–III TNBC with no previous therapy for potentially curative surgery—they were randomly assigned to two groups; group I was treated with 50 mg veliparib orally twice a day, with 12 weekly doses of 80 mg/m2 intravenous paclitaxel, and carboplatin administered every 3 weeks, for 4 cycles [43][44][45]. Patients with a germline BRCA mutation were then allocated to group II and administered cyclophosphamide and doxorubicin every 2–3 weeks for 4 rounds [44]. Effective clinical outcomes were observed to be higher in 53% of patients with combined therapies in comparison to patients who received paclitaxel alone (31%). No significant toxicity was observed against Veliparib. [43][44][45].

2.5. Talazoparib (BMN-673)

Talazoparib is a PARP inhibitor that is hypothesized to have a higher effectiveness than olaparib due to the process of PARP trapping, in which a PARP molecule is trapped on the DNA, inhibiting cell division [46]. Talazoparib is a dual-mechanism PARP inhibitor that traps PARP on DNA [46][47]. The phase II study ABRAZO evaluated the efficacy of talazoparib on inpatients with germline BRCA1/2 mutations before being treated with platinum or multiple regimens [46][47]. Clinical efficacy was evaluated in TNBC/HR+ patients at 26%/29%; adverse effects were observed such as neutropenia, thrombocytopenia, anemia, fatigue, nausea, and diarrhea [47]. A phase III clinical trial was performed to compare the efficacy and safety of talazoparib in TNBC patients [46][47][48]. Clinical efficacy was observed—median PFS was 8.6 months for talazoparib, with a 46% reduction in the tumor, and 5.6 months for chemotherapies such as capecitabine, eribulin, gemcitabine, or vinorelbine [46][47][48]. All key secondary efficacy endpoints (OS, ORR, clinical benefit rate at 24 weeks) demonstrated benefits with talazoparib [47][48]. The PARP inhibitor was generally well tolerated, with minimal non-hematologic toxicity and few adverse events associated with treatment discontinuations [46][47][48]. Patients were treated with an anthracycline, with or without taxane as a neoadjuvant [46]; its primary clinical efficacy was examined, with PFS performed according to RECIST 1.1 criteria: median PFS was 8.6 and 5.6 months in the talazoparib and chemotherapy arms, respectively (HR 0.54; 95% CI: 0.41, 0.71; p < 0.0001) [47][48]. Its clinical approval was considered in EMBRACA (NCT01945775), an open label trial randomizing 431 patients (2:1) who were gBRCAHER2-negative to treatment with talazoparib (1 mg) with no more than 3 prior cytotoxic chemotherapy treatments for metastatic disease. Talazoparib was approved by the FDA for germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer. The FDA also approved the BRAC Analysis CDx test for identifying patients with breast cancer with deleterious or suspected deleterious gBRCAm who are eligible for talazoparib [47].

2.6. Rucaparib

Rucaparib is an effective inhibitor of PARP1, PARP-2, and PARP-3 in BRCA-mutated patients (germline and/or somatic). Rucaparib was also found to be effective in HR-deficient patients [49]. Rucaparib is indicated as a monotherapy treatment for adults who are platinum-sensitive, patients who have been treated with two or more prior lines of platinum-based chemotherapy, and for those who are unable to tolerate further platinum-based chemotherapy [50]. A multicenter phase clinical trial was performed to establish BRCA1/2 mutations and earlier treatment with rucaparib. Intravenous, and subsequently oral, rucaparib were evaluated with different dose concentrations [51]. Efficacy and safety levels were evaluated, such as pharmacodynamics, pharmacokinetic dose-limiting toxic effects, and tolerability [52]. Intravenous rucaparib was given and the objective response rate was analyzed: 41% of patients showed an ongoing response for at least 12 weeks [53]. The efficacy and safety of rucaparib in patients with HER2-negative metastatic breast cancer were associated with BRCAness phenotype and/or a somatic BRCA mutations [49][50][51][52][53]. Patients received 600 mg rucaparib orally for 21 days or up to the development of the disease. The main endpoint was the clinical benefit rate and secondary endpoints, including PFS, overall survival, safety, and the prognostic value of the BRCAness signature [49][50][51][52][53]. An additional study determined the quantity of sporadic TNBC patients likely to benefit from rucaparib treatment [49][50][51][52][53].

2.7. Checkpoint Inhibitors

TNBC is pushing to improve treatment by answering questions regarding biomarkers of response, defining the utility of neoadjuvant approaches, and exploring potential combinations of checkpoint inhibitors and PARP inhibitors. The FDA approved the nab-paclitaxel (Abraxane) with atezolizumab (Tecentriq) for patients with metastatic PD-L1-positive TNBC. The approval was based on the phase 3 IMpassion130 trial (NCT02425891), which established a 38% decrease in the risk of disease development with the combination vs. placebo plus nab-paclitaxel in this patient population. Pembrolizumab is a second approved checkpoint inhibitor drug, approved by the FDA in Nov 2020, for patients with metastatic TNBC whose tumors express a PD-L1 combined positive score (CPS) of 10 or higher, as determined by an FDA-approved test. Pembrolizumab also demonstrated proof of concept as a neoadjuvant based on findings from the phase II I-SPY2 trial (NCT01042379); pembrolizumab neoadjuvant plus chemotherapy extended pathologic complete response (pCR) rates by 13.6 percentage points compared with chemotherapy alone for patients with early TNBC (95% CI, 5.4–21.8; p < 0.001).

References

  1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.
  2. Rummel, S.K.; Lovejoy, L.; Shriver, C.D.; Ellsworth, R.E. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res. Treat. 2017, 164, 593–601.
  3. Singh, D.D.; Yadav, D.K. TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy. Biomedicines 2021, 9, 876.
  4. Medina, M.A.; Oza, G.; Sharma, A.; Arriaga, L.G.; Hernández Hernández, J.M.; Rotello, V.M.; Ramirez, J.T. Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. Int. J. Environ. Res. Public Health 2020, 17, 2078.
  5. Lee, K.-L.; Chen, G.; Chen, T.-Y.; Kuo, Y.-C.; Su, Y.-K. Effects of Cancer Stem Cells in Triple-Negative Breast Cancer and Brain Metastasis: Challenges and Solutions. Cancers 2020, 12, 2122.
  6. Lee, K.-L.; Kuo, Y.-C.; Ho, Y.-S.; Huang, Y.-H. Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness. Cancers 2019, 11, 1334.
  7. Nederlof, I.; Horlings, H.; Curtis, C.; Kok, M. A High-Dimensional Window into the Micro-Environment of Triple Negative Breast Cancer. Cancers 2021, 13, 316.
  8. Keung, M.Y.T.; Wu, Y.; Vadgama, J.V. PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. J. Clin. Med. 2019, 8, 435.
  9. Schettini, F.; Giudici, F.; Bernocchi, O.; Sirico, M.; Corona, S.P.; Giuliano, M.; Locci, M.; Paris, I.; Scambia, G.; De Placido, S.; et al. Poly (ADP-ribose) polymerase inhibitors in solid tumours: Systematic review and meta-analysis. Eur. J. Cancer 2021, 149, 134–152.
  10. Gourley, C.; Balmaña, J.; Ledermann, J.A.; Serra, V.; Dent, R.; Loibl, S.; Pujade-Lauraine, E.; Boulton, S.J. Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J. Clin. Oncol. 2019, 37, 2257–2269.
  11. van Beek, L.; McClay, É.; Patel, S.; Schimpl, M.; Spagnolo, L.; de Oliveira, T.M. PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling. Int. J. Mol. Sci. 2021, 22, 5112.
  12. Langelier, M.-F.; Planck, J.L.; Roy, S.; Pascal, J.M. Structural Basis for DNA Damage-Dependent Poly(ADP-Ribosyl)Ation by Human PARP-1. Science 2012, 336, 728–732.
  13. Pascal, J.M. The Comings and Goings of PARP-1 in Response to DNA Damage. DNA Repair 2018, 71, 177–182.
  14. Wang, Y.; Luo, W.; Wang, Y. PARP-1 and Its Associated Nucleases in DNA Damage Response. DNA Repair 2019, 81, 102651.
  15. Van Andel, L.; Zhang, Z.; Lu, S.; Kansra, V.; Agarwal, S.; Hughes, L.; Tibben, M.M.; Gebretensae, A.; Lucas, L.; Hillebrand, M.J.X.; et al. Human mass balance study and metabolite profiling of 14Cniraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer. Investig. New Drugs 2017, 35, 751–765.
  16. Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. N. Engl. J. Med. 2009, 361, 123–134.
  17. Virtanen, V.; Paunu, K.; Ahlskog, J.K.; Varnai, R.; Sipeky, C.; Sundvall, M. PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development. Genes 2019, 10, 565.
  18. Dirix, L.; Swaisland, H.; Verheul, H.M.; Rottey, S.; Leunen, K.; Jerusalem, G.; Rolfo, C.; Nielsen, D.; Molife, L.R.; Kristeleit, R.; et al. Effect of itraconazole and rifampin on the pharmacokinetics of olaparib in patients with advanced solid tumors: Results of two phase I open-label studies. Clin. Ther. 2016, 38, 2286–2299.
  19. Plummer, R.; Swaisland, H.; Leunen, K.; Van Herpen, C.M.L.; Jerusalem, G.; De Greve, J.; Lolkema, M.P.; Soetekouw, P.; Mau-Sørensen, M.; Nielsen, D.; et al. Olaparib tablet formulation: Effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 2015, 76, 723–729.
  20. Mostafa, N.M.; Chiu, Y.L.; Rosen, L.S.; Bessudo, A.; Kovacs, X.; Giranda, V.L. A phase 1 study to evaluate effect of food on veliparib pharmacokinetics and relative bioavailability in subjects with solid tumors. Cancer Chemother. Pharmacol. 2014, 74, 583–591.
  21. Tuli, R.; Shiao, S.L.; Nissen, N.; Tighiouart, M.; Kim, S.; Osipov, A.; Bryant, M.; Ristow, L.; Placencio-Hickok, V.; Hoffman, D.; et al. A Phase 1 Study of Veliparib, a PARP-1/2 Inhibitor, with Gemcitabine and Radiotherapy in Locally Advanced Pancreatic Cancer. EBioMedicine 2019, 40, 375–381.
  22. Andreidesz, K.; Koszegi, B.; Kovacs, D.; Bagone Vantus, V.; Gallyas, F.; Kovacs, K. Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2021, 22, 2056.
  23. Sari, M.; Saip, P. Myelodysplastic Syndrome after Olaparib Treatment in Heavily Pretreated Ovarian Carcinoma. Am. J. Ther. 2019, 26, e632–e633.
  24. Murai, J.; Huang, S.-Y.N.; Renaud, A.; Zhang, Y.; Ji, J.; Takeda, S.; Morris, J.; Teicher, B.; Doroshow, J.H.; Pommier, Y. Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib. Mol. Cancer Ther. 2014, 13, 433–443.
  25. Robson, M.; Im, S.-A.; Senkus, E.; Xu, B.; Domchek, S.M.; Masuda, N.; Delaloge, S.; Li, W.; Tung, N.; Armstrong, A.; et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med. 2017, 377, 523–533.
  26. Nicolas, E.; Bertucci, F.; Sabatier, R.; Gonçalves, A. Targeting BRCA Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives? Cancers 2018, 10, 506.
  27. Clarke, N.; Wiechno, P.; Alekseev, B.; Sala, N.; Jones, R.; Kocak, I.; Chiuri, V.E.; Jassem, J.; Flechon, A.; Redfern, C.; et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018, 19, 975–986.
  28. Robson, M.; Tung, N.; Conte, P.; Im, S.-A.; Senkus, E.; Xu, B.; Masuda, N.; Delaloge, S.; Li, W.; Armstrong, A.; et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol. 2019, 30, 558–566.
  29. Pujade-Lauraine, E.; Ledermann, J.A.; Selle, F. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, E510.
  30. Karzai, F.; VanderWeele, D.; Madan, R.A.; Owens, H.; Cordes, L.M.; Hankin, A.; Couvillon, A.; Nichols, E.; Bilusic, M.; Beshiri, M.L.; et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J. Immunother. Cancer 2018, 6, 141.
  31. Nitecki, R.; Gockley, A.A.; Floyd, J.L.; Coleman, R.L.; Melamed, A.; Rauh-Hain, J.A. The incidence of myelodysplastic syndrome in patients receiving poly-ADP ribose polymerase inhibitors for treatment of solid tumors: A meta-analysis. J. Clin. Oncol. 2020, 38, 3641.
  32. Hossain, F.; Majumder, S.; David, J.; Miele, L. Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions. Cancers 2021, 13, 3739.
  33. Bergin, A.R.T.; Loi, S. Triple-negative breast cancer: Recent treatment advances. F1000Research 2019, 8, 1342.
  34. Pierce, A.; McGowan, P.M.; Cotter, M.; Mullooly, M.; O’Donovan, N.; Rani, S.; O’Driscoll, L.; Crown, J.; Duffy, M.J. Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines. Cancer Biol. Ther. 2013, 14, 537–545.
  35. Telli, M.L.; Timms, K.M.; Reid, J.; Hennessy, B.; Mills, G.B.; Jensen, K.C.; Szallasi, Z.; Barry, W.T.; Winer, E.P.; Tung, N.M.; et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 2016, 22, 3764–3773.
  36. Diéras, V.; Bonnefoi, H.; Alba, E.; Awada, A.; Coudert, B.; Pivot, X.; Gligorov, J.; Jager, A.; Zambelli, S.; Lindeman, G.J.; et al. Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: A phase II randomized open-label study with pharmacokinetics. Breast Cancer Res. Treat. 2019, 177, 383–393.
  37. Mateo, J.; Ong, M.; Tan, D.S.; Gonzalez, M.A.; de Bono, J.S. Appraising iniparib, the PARP inhibitor that never was—What must we learn? Nat. Rev. Clin. Oncol. 2013, 10, 688–696.
  38. O’Shaughnessy, J.; Schwartzberg, L.; Danso, M.A.; Miller, K.D.; Rugo, H.S.; Neubauer, M.; Robert, N.; Hellerstedt, B.; Saleh, M.; Richards, P.; et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J. Clin. Oncol. 2014, 32, 3840–3847.
  39. González-Martín, A.; Pothuri, B.; Vergote, I.; DePont Christensen, R.; Graybill, W.; Mirza, M.R.; McCormick, C.; Lorusso, D.; Hoskins, P.; Freyer, G.; et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2391–2402.
  40. Sandhu, S.K.; Schelman, W.R.; Wilding, G.; Moreno, V.; Baird, R.D.; Miranda, S.; Hylands, L.; Riisnaes, R.; Forster, M.; Omlin, A.; et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: A phase 1 dose-escalation trial. Lancet Oncol. 2013, 14, 882–892.
  41. Vinayak, S.; Tolaney, S.M.; Schwartzberg, L.; Mita, M.; McCann, G.; Tan, A.R.; Wahner-Hendrickson, A.E.; Forero, A.; Anders, C.; Wulf, G.M.; et al. Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol. 2019, 5, 1132–1140.
  42. Appleman, L.J.; Beumer, J.H.; Jiang, Y.; Lin, Y.; Ding, F.; Puhalla, S.; Swartz, L.; Owonikoko, T.K.; Donald Harvey, R.; Stoller, R.; et al. Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies. Cancer Chemother. Pharmacol. 2019, 84, 1289–1301.
  43. Loibl, S.; O’Shaughnessy, J.; Untch, M.; Sikov, W.M.; Rugo, H.S.; McKee, M.D.; Huober, J.; Golshan, M.; von Minckwitz, G.; Maag, D.; et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): A randomised, phase 3 trial. Lancet Oncol. 2018, 19, 497–509.
  44. Diéras, V.; Han, H.S.; Kaufman, B.; Wildiers, H.; Friedlander, M.; Ayoub, J.-P.; Puhalla, S.L.; Bondarenko, I.; Campone, M.; Jakobsen, E.H.; et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020, 21, 1269–1282.
  45. Han, H.S.; Diéras, V.; Robson, M.; Palácová, M.; Marcom, P.K.; Jager, A.; Bondarenko, I.; Citrin, D.; Campone, M.; Telli, M.L.; et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: Randomized phase II study. Ann. Oncol. 2018, 29, 154–161.
  46. de Bono, J.; Ramanathan, R.K.; Mina, L.; Chugh, R.; Glaspy, J.; Rafii, S.; Kaye, S.; Sachdev, J.; Heymach, J.; Smith, D.C.; et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov. 2017, 7, 620–629.
  47. Litton, J.K.; Hurvitz, S.A.; Mina, L.A.; Rugo, H.S.; Lee, K.-H.; Gonçalves, A.; Diab, S.; Woodward, N.; Goodwin, A.; Yerushalmi, R.; et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: Final overall survival results from the EMBRACA trial. Ann. Oncol. 2020, 31, 1526–1535.
  48. Litton, J.K.; Scoggins, M.E.; Hess, K.R.; Adrada, B.E.; Murthy, R.K.; Damodaran, S.; DeSnyder, S.M.; Brewster, A.M.; Barcenas, C.H.; Valero, V.; et al. Neoadjuvant Talazoparib for Patients with Operable Breast Cancer with a Germline BRCA Pathogenic Variant. J. Clin. Oncol. 2020, 38, 388–394.
  49. Miller, K.; Tong, Y.; Jones, D.R.; Walsh, T.; Danso, M.A.; Ma, C.X.; Silverman, P.; King, M.-C.; Badve, S.S.; Perkins, S.M. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: Final efficacy results of Hoosier Oncology Group BRE09-146. J. Clin. Oncol. 2015, 33, 1082.
  50. Drew, Y.; Ledermann, J.; Hall, G.; Rea, D.; Glasspool, R.; Highley, M.; Jayson, G.; Sludden, J.; Murray, J.; Jamieson, D.; et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br. J. Cancer 2016, 114, 723–730.
  51. Durmus, S.; Sparidans, R.W.; van Esch, A.; Wagenaar, E.; Beijnen, J.H.; Schinkel, A.H. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699). Pharm. Res. 2015, 32, 37–46.
  52. Simmons, A.D.; Nguyen, M.; Pintus, E. Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: A case report. BMC Cancer 2020, 20, 215.
  53. FDA. Grants Accelerated Approval to Rucaparib for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer. Available online: https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistantprostate (accessed on 15 July 2021).
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