Role of PARP in TNBC | Encyclopedia MDPI

Role of PARP in TNBC: Comparison

Please note this is a comparison between Version 1 by Dharmendra Kumar Yadav and Version 2 by Vivi Li.

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][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][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][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][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]}[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][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 1, Table 2 and Table 3).

Table 1. List of PARP inhibitors.

Compound Name	Compound Structure	Efficacy	IC₅₀

Table 2. Efficacy of PARP inhibitors.

Name of the Molecules	T_max (h)	t (h)	AUC (lgh/ mL)	C_max (lg/mL)	CL/F (L/h)	V_z/F	References
Nicotinamide		PARP inhibitor and by-product of the PARP reaction; many pharmacological actions other than that of inhibiting PARP	210 μM
3-aminobenzamide		Benzamides are free radical scavengers, among other
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)	pharmacological actions	33 μM
PD128763		Cytoprotective agent, chemosensitizer, and radiosensitizer; adverse effect of compound causes hypothermia	420 nM
	[AUC]	5.48 (40.5)	7.55 (3.99)	127 (107)	^[19	DPQ		A commonly used Warner–Lambert PARP inhibitor compound based on an isoquinoline core	1 μM
NU1025		Potentiators of anticancer agent cytotoxicity	400 nM
4-ANI		PARP in DNA repair and cell death	180 nM
^]	INO-1001		Potent enhancer of radiation sensitivity and enhances radiation-induced cell killing by interfering with DNA repair mechanisms, resulting in necrotic cell death	105 nM
Veliparib monotherapy 40 mg (10 mg, fasting)	E7449		Antitumor activity of E7449; a novel PARP 1/2 and tankyrase 1/2 inhibitor	1 nM
CEP-8983		Increases the sensitivity of chemoresistant tumor cells to temozolomide	20 nM
^[	¹⁸	^]
Olaparib tablet formulation 300 mg single dose (fasted)	1.50 (0.50–5.85)	12.2 (5.31)	43.6 (54.3) [AUC_t] 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) [AUC_t	Pamiparib (BGB-290)		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
]		45.4 (57.1)1.2 ± 0.8	5.9 ± 1.3	2.23 ± 0.82 [AUC_t] 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 [AUC_t] 2.65 ± 1.17 [AUC_t]	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 [AUC_t] 2.45 ± 1.24 [AUC_t]	0.34 ± 0.12	19.5 ± 7.66	NA	ISO
Veliparib monotherapy 40 mg (40 mg, fed)	PARP in DNA repair and cell death	390 nM
2.5 ± 1.1	5.8 ± 1.4	2.14 ± 0.80 [AUC_t] 2.35 ± 1.06 [AUC_t]	0.28 ± 0.09	19.7 ± 7.51	NA	Olaparib (Lynparza)		Use in a BRCA1
Veliparib metabolite M8	2.4 (3.5–9.8)-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
–	0.3–1.9 [AUC_int]	0.011 (0.007–0.014)	NA	NA	^[20]^[21]	Niraparib (Zejula)		Niraparib in combination with pembrolizumab in patients with triple-negative breast cancer	4 nM
Niraparib 300 mg/day	3.1 (2.0–6.1)	a	14.117 (AUC24)b	1.921	NA	NA^[12]	Talazoparib (Talzenna)		Ferm line BRCA-mutant, HER2-negative locally advanced or metastatic breast cancer	0.6 nM
Niraparib metabolite: unlabeled M1 plasma	9.02	78.4	41.2 (AUC_t)	476	NA	NA	^[15]	Veliparib (ABT-888)		Received orphan drug status for lung cancer	2 nM	Fluzoparib (SHR-3162)	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 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 EGFR, HER2, BRCA, 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 EGFR, BRCA, and tyrosine kinase	Veliparib with vinorelbine	Patients with TNBC	Completed phase I	NCT01281150
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, and tyrosine kinase	Veliparib with cisplatin	Patients with TNBC	Completed phase I	NCT01104259
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, and tyrosine kinase	Veliparib with pegylation	Patients with TNBC	Completed phase I	NCT01145430
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, and tyrosine kinase	Veliparib with pegylation	Patients with TNBC	Completed phase I	NCT01145430
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, and tyrosine kinase	Veliparib with lapatinib	Patients with TNBC	Phase I	NCT02158507
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, and tyrosine kinase	Veliparib in combination with irinotecan HCl	Patients with TNBC	Phase I I	NCT00576654
PARP1/2 inhibitor Veliparib	Inhibitor of EGFR, HER2, BRCA, 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 EGFR, HER2, BRCA, 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][29]. A multicentric clinical evaluation of olaparib was carried out using it as a monotherapy for inpatients with germline BRCA1/2 mutations ^[23][24][25][56,62,63]. 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]}[64,65,66,67,68]. 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]}[65,66,67,68]. A phase 3 clinical trial employed olaparib monotherapy in germline BRCA mutations with HER2 negativity and, at minimum, previous chemotherapy therapy ^[29][67]. 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]}[3,64,65,66]. 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]}[3,66,67,68]. 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]}[66,67,68,69]. 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][65,66]. Olaparib is mainly excreted through urine (44%) and feces (42%) ^[28][66].

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][64]. Olaparib was the first PARP inhibitor to establish higher efficacy and tolerability than standard chemotherapy in gBRCA-mutated advanced BC ^{[27][28][29][30]}[65,66,67,68]. 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][68,69,70]. 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][71,72,73]. 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][66,73].

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][74,75]. 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][70,71,72]. Iniparib used together with a PARP-1 inhibitor has also shown efficacy in DNA repair mechanisms ^[34][72]. One clinical trial investigated patients with metastatic TNBC ^[36][37][74,75], 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][74,76]. 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][76].

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][73,77]. 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][73,77]. Niraparib was extended for use in the care treatment of adults following first-line platinum-based chemotherapy ^[29][35][67,73].

Patients with solid tumors (BRCA1 or BRCA2 mutation carrier) were enrolled in a phase I clinical trial ^{[38][39][40][41]}[76,77,78,79]. 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]}[76,77,78,79]. No safety concerns have been noted by the IDMC (Independent Data Monitoring Committee) concerning niraparib ^{[38][39][40][41]}[76,77,78,79]. 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]}[76,77,78,79].

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][80]. Veliparib is effective in platinum-based therapy in xenograft models ^[42][43][80,81]. 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][82,83]. 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][81,82,83]. 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][81,82,83]. 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][81,82,83]. 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][83]. 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][83]. 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][81,82,83]. 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][82]. 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][81,82,83].

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][84]. Talazoparib is a dual-mechanism PARP inhibitor that traps PARP on DNA ^[46][47][84,85]. 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][84,85]. 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][85]. A phase III clinical trial was performed to compare the efficacy and safety of talazoparib in TNBC patients ^[46][47][48][84,85,86]. 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][84,85,86]. All key secondary efficacy endpoints (OS, ORR, clinical benefit rate at 24 weeks) demonstrated benefits with talazoparib ^[47][48][85,86]. The PARP inhibitor was generally well tolerated, with minimal non-hematologic toxicity and few adverse events associated with treatment discontinuations ^[46][47][48][84,85,86]. Patients were treated with an anthracycline, with or without taxane as a neoadjuvant ^[46][84]; 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][85,86]. Its clinical approval was considered in EMBRACA (NCT01945775), an open label trial randomizing 431 patients (2:1) who were gBRCAm HER2-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][85].

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][87]. 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][88]. 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][89]. Efficacy and safety levels were evaluated, such as pharmacodynamics, pharmacokinetic dose-limiting toxic effects, and tolerability ^[52][90]. Intravenous rucaparib was given and the objective response rate was analyzed: 41% of patients showed an ongoing response for at least 12 weeks ^[53][91]. 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]}[87,88,89,90,91]. 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]}[87,88,89,90,91]. An additional study determined the quantity of sporadic TNBC patients likely to benefit from rucaparib treatment ^{[49][50][51][52][53]}[87,88,89,90,91].

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).