In the field of DNA damage repair and breast cancer, particularly TNBC, the key molecular players are most notably p53 and BRCA1/2. Mutations in p53 can influence the expression of key genes associated with cell proliferation, including MYC proto-oncogene, bHLH transcription factor, C-X-C motif chemokine ligand 1 and cyclin E2, through direct or indirect pathways (31–33). Although TP53 is the most frequently altered gene in breast cancer, p53 remains in its wild-type form >2/3 of cases. However, in basal-like breast cancer cases, most of which are triple negative, the mutation frequency of p53 reaches 88% (34). BRCA1 and BRCA2 are tumor suppressor genes linked to breast cancer, playing essential roles in homologous recombination repair (HRR). Mutations in BRCA1 are frequently observed in patients with breast cancer, resulting in defects in DNA repair, abnormal centrosome replication, and impaired cell cycle and spindle checkpoint functions. This has led to the hypothesis that BRCA1 mutations contribute to tumorigenesis through genomic instability (35). These mutations not only endow cells with malignant potential but also allow the use of targeted therapies.

The concept of synthetic lethality refers to the phenomenon where two different metabolic pathways or gene functions compensate for one another; inhibiting either pathway alone does not result in cell death, but simultaneous inhibition of both leads to cell death, which also applies to tumor cells (36). Mutations in the p53 and BRCA1/2 genes in patients disable one of the primary DNA repair pathways, and further inhibition of the DNA repair function of PARP leads to pronounced cell death (37). This theory has been validated in numerous experiments. For instance, Bryant et al (38) demonstrated that BRCA2 deficiency (either BRCA2^+/− or BRCA2^−/−) resulted in HRR defects, and mice with BRCA2 mutations showed a high sensitivity to PARP inhibitors, which induced replication fork collapse and selectively killed the defective cells, while cells with normal BRCA function remained largely unaffected. Farmer et al (39) elucidated the mechanism involving the interaction between BRCA2 and RAD51, highlighting that the rapid recruitment of RAD51 to DNA damage sites was fundamental to the HRR pathway. While PARP1 does not play a direct role in HRR, its absence increases the need for an efficient HRR pathway, possibly due to the conversion of unrepaired SSBs into double-strand breaks. Normally, BRCA2 recruits RAD51 to these sites for HRR, but without functional BRCA2, HRR does not occur (39).

BRCA1-associated ring domain 1 (BARD1) is a protein that forms a heterodimer with BRCA1 and plays a crucial role in DNA damage repair. Regarding the mechanism by which BRCA molecules are recruited to DNA damage sites, the role of BARD1 has been widely recognized. BARD1, the primary partner of BRCA1, contains tandem BRCT motifs. The heterodimer of BARD1 and BRCA1 is targeted to sites of DNA damage mainly through their ring-like structures, while the BRCT domains, which recognize phosphorylated serine motifs, influence the translocation of the dimer at DNA sites (40,41). Additionally, the interaction between BRCT and PAR occurs through the binding of each ADP-ribose unit in PAR, thereby ensuring the adequate progression of HRR (42,43).

Protein ubiquitination not only plays a key role in protein degradation but also has crucial functions in DNA damage repair and maintaining genomic stability. A study has shown that checkpoint protein with FHA and RING domains (CHFR), through its interaction with PARP1, regulates the crosstalk between PARylation and ubiquitination. PARP1 recruits downstream DNA repair factors via PAR modification, while CHFR may regulate the ubiquitination of PAR and repair proteins, thereby modulating the duration and intensity of PARP1 activity during the DNA damage repair process (44). This coordinated regulation is critical to ensure the accuracy and timeliness of DNA damage repair, and it may also confer sensitivity to PARP inhibitors in TNBC cells (45). Furthermore, a diverse range of ubiquitin ligases have been identified, including deltex E3 ubiquitin ligase (DTX), ring finger protein 8(RNF8) and mediator of DNA damage checkpoint 1(MDC1) (46–49). The combined use of drugs targeting ubiquitin ligases exacerbates the accumulation of DNA damage, leading to unrepaired DNA breaks in cancer cells, ultimately triggering cell death.

Epigenetic modifications refer to alterations in gene expression that do not involve changes to the DNA sequence itself. Common epigenetic modifications include DNA methylation and histone modifications (such as acetylation, methylation and phosphorylation), which regulate gene expression by altering chromatin structure (50). One of the central mechanisms of epigenetic regulation involves modifying chromatin conformation to control gene accessibility. PARP-1 and other members of the PARP family modulate chromatin plasticity through the PARylation of histones (51,52). For example, previous research has shown that histones such as H2A at K13, H2B at K30, H3 at K27 and K37, and H4 at K16 can serve as ADP-ribose acceptor sites (53). The PARylation of H2 introduces a considerable negative charge around chromatin proteins, leading to chromatin decondensation, thereby facilitating the access of DNA repair factors to sites of damage (54). Zhou et al (55) treated trophoblast stem cells with a DNA-modifying agent in PAR glycohydrolase-deficient cells and found that excessive PARylation of histones, due to inhibition of PAR chain hydrolysis, increased the sensitivity of the cells to DNA damage-induced cell death.

Activation of PARP-1 can also alter chromatin structure by recruiting chromatin remodeling complexes such as the Switch/sucrose non-fermentable complex, which plays a critical role in regulating chromatin structure and gene expression by altering chromatin accessibility (56). However, in tumor cells, this can more easily induce synthetic lethality (57). It is worth noting that PARylation can activate gene expression but can also regulate gene silencing through chromatin compaction. For instance, SIRT1, a deacetylase that promotes cell survival, competes with PARP-1 as both rely on NAD+ as a substrate. Overactivation of PARP-1 can reduce SIRT1 activity, thereby contributing to gene silencing (58). Previous research has suggested that certain viruses can exploit PARP-1 to modify viral episomes or host genes, aiding long-term viral infections of DNA viruses, which can lead to tumorigenesis (59).

Long non-coding RNAs (lncRNAs) are also involved in the epigenetic regulation of gene expression by interacting with epigenetic regulatory protein complexes, such as histone-modifying enzymes and DNA methyltransferases, and are closely associated with apoptosis, autophagy and transformation. Increasing evidence has revealed their role in promoting tumor initiation, invasion and malignancy (60–62). A PAR-related study has reported that a human lncRNA-encoded micropeptide called PACMP not only inhibits the ubiquitination of C-terminal binding protein-interacting protein by blocking its interaction with KLHL15 but also directly binds to DNA damage-induced PAR chains, thus enhancing PARP1-dependent PARylation. Targeting lnc15.2/PACMP has shown reversal of resistance to several chemotherapy drugs, including PARP inhibitors, ataxia telangiectasia and Rad3-related inhibitors and cyclin-dependent kinase-4/6 inhibitors (63). However, there is limited research on targeted therapy of lncRNAs related to breast cancer in combination with PARP inhibitors, thus offering a broad scope for exploration in the future.

Iniparib (chemical name: BSI-201) was initially considered one of the promising candidate drugs in the category of PARP inhibitors. In 2011, it entered phase II clinical trials and demonstrated significant efficacy in treating TNBC (clinical trial no. NCT00540358) (77). However, subsequent phase III randomized controlled trials (clinical trial no. NCT00938652) (78) delivered disappointing results. In the trial, 261 patients treated with the combination of gemcitabine + carboplatin + Iniparib were compared with 258 patients receiving gemcitabine + carboplatin alone, and no statistically significant difference was observed in overall survival (OS) [hazard ratio (HR)=0.88; 95% confidence interval (CI), 0.69–1.12; P=0.28] or progression-free survival (PFS) (HR=0.79; 95% CI, 0.65–0.98; P=0.027). These results indicated that the potential benefits of Iniparib required further evaluation (78).

Subsequent analysis of these results, which was conducted by Mateo et al (79), suggested that Iniparib is not a true PARP inhibitor. The authors also proposed a framework for identifying potential ‘pitfalls’ in anticancer drug development. In fact, Liu et al (80) pointed out that the primary mechanism of action of Iniparib may be through non-selectively modifying cysteine-containing proteins in tumor cells. This modifying effect does not rely on the catalytic mechanism of PARP. Instead, it affects the survival and proliferation of tumor cells through other pathways.

Olaparib (chemical name: AZD2281), developed by AstraZeneca, is the first widely used PARP inhibitor in clinical settings. Its earliest clinical trials began in 2005, focusing on breast and ovarian cancer cases with BRCA1/2 mutations, and it also showed efficacy in HER2-negative metastatic breast cancer (81). In 2009, the results of a phase I clinical trial (clinical trial no. NCT00516373) demonstrated the effectiveness of Olaparib in BRCA-mutated ovarian and breast cancer (23). Subsequently, a phase II, multicenter, open-label, non-randomized study (clinical trial no. NCT00679783) was conducted to evaluate Olaparib treatment in women with ovarian cancer and TNBC. The results showed that 18 out of 64 patients with ovarian cancer had a confirmed objective response, while no responses were observed in any of the 26 patients with TNBC (15). Similarly, a multicenter phase II clinical study in 2015 reported the therapeutic response in germline BRCA1/2-mutated tumors, with a relatively low response rate of 12.9% (8/62; 95% CI, 5.7–23.9) in breast cancer. Additionally, 47% of the patients experienced stable disease for >8 weeks (95% CI, 34.0–59.9) (82).

Whether used as a monotherapy or in combination with other drugs, the majority of the early clinical studies reported that ≥50% of patients experienced grade ≥3 adverse events (82–86). Previous studies have also evaluated the safety and tolerability of combining Olaparib with radiotherapy. For instance, Loap et al (87–89) conducted the long-term RADIOPARP phase I trial in 24 patients with TNBC who exhibited residual disease after neoadjuvant chemotherapy. These patients were treated with four different doses of Olaparib (50, 100, 150 and 200 mg, twice daily). Initially, no dose-limiting toxicities were observed, and after 1 year of follow-up, no treatment-related grade ≥3 toxicities were noted. Additionally, the 3-year OS and event-free survival rates were 83% (95% CI, 70–100%) and 65% (95% CI, 48–88%), respectively.

In recent years, the majority of clinical trials involving Olaparib have progressed to phase II or III (Table I). Based on the trial endpoints, it can be observed that Olaparib has improved pathological complete response and OS in patients, although the improvements are not always statistically significant. Additionally, certain studies have not only focused on efficacy but also on quality of life (QoL). For example, a patient-reported outcomes study indicated that patients receiving Olaparib experienced statistically significantly higher levels of fatigue at 6 and 12 months during the treatment and follow-up periods compared to those receiving placebo. However, this did not reach the predetermined clinical significance threshold of a 3-point difference. At 18 and 24 months, the Olaparib and placebo scores were similar (90). In conclusion, the importance of these clinical studies lies in helping physicians make more precise decisions about treatment options by considering both QoL and efficacy, ensuring that therapeutic effectiveness is maximized while minimizing the burden on the QoL of patients.

The earliest clinical study on Rucaparib (chemical name: AG-014699) was reported in 2008, when Plummer et al (91) evaluated the safety, efficacy, pharmacokinetics and pharmacodynamics of AG-014699 in combination with temozolomide in adult patients with advanced malignant tumors. The study observed encouraging evidence of activity. In 2016, clinical research focusing on breast cancer-related treatments indicated that Rucaparib was well tolerated at doses ≤480 mg/day and was a potent PARP inhibitor, providing sustained inhibition for ≥24 h after a single dose, although specific efficacy data for patients with breast cancer were not provided (92).

Another phase II clinical trial in patients with TNBC found that Rucaparib significantly reduced circulating tumor DNA levels in homologous recombination repair-deficient cancer and induced the expression of interferon response genes, suggesting that Rucaparib may enhance antitumor effects not only through inhibition of DNA repair pathways but also by triggering DNA damage-induced immune responses (93). In another study, Kristeleit et al (94) evaluated the combination of Rucaparib with the immune checkpoint inhibitor Atezolizumab in advanced gynecological cancer or TNBC. Patients with higher PD-L1 levels and BRCA mutations prior to treatment were more likely to experience adverse reactions such as gastrointestinal symptoms, elevated levels of liver enzymes or anemia. Markers of DNA damage repair (such as RAD51 foci) and apoptosis markers were also reduced. This suggests that there may be a synergistic effect between the immune response and PARP inhibitors. Rucaparib may enhance tumor antigen production by promoting DNA damage, thereby activating the immune system.

Niraparib (chemical name: MK-4827) is an oral, potent and selective inhibitor of PARP-1 and PARP-2, capable of inducing functional loss in BRCA and phosphatase and tensin homolog. In 2013, Sandhu et al (95) clinically evaluated its safety and tolerability, establishing 300 mg/day as the maximum tolerated dose. The oral bioavailability of Niraparib in humans was measured at 72.7% (96). In the multi-country, phase III Niraparib in Patients with Platinum-Sensitive Recurrent Ovarian Cancer trial (NCT01847274) conducted in adult patients with platinum-sensitive recurrent ovarian cancer (97), Niraparib significantly prolonged the median PFS, regardless of the presence of germline BRCA mutations or HRD, highlighting its distinct advantage (98).

Although clinical research on the treatment of TNBC with Niraparib remains limited, a combination therapy study involving Niraparib (MK-4827) and fractionated radiotherapy in the MDA-MB-231 TNBC cell line has demonstrated promising results. Regardless of p53 status, MK-4827 reduced tumor PAR levels within 1 h of administration, with the effect lasting ≤24 h (99). These findings provide a foundation for future research in this area.

Talazoparib (chemical name: BMN673), developed by BioMarin Pharmaceutical Inc., is a second-generation PARP inhibitor. Previous research has shown that BMN673 exhibits selective cytotoxicity against tumor cells and induces DNA repair biomarkers at notably lower concentrations compared to first-generation PARP1/2 inhibitors such as Olaparib, Rucaparib and Veliparib (PARP1 half-maximal inhibitory concentration, 0.57 nmol/l) (100). In a 2017 phase I clinical trial (clinical trial no. NCT01286987), Talazoparib demonstrated notable antitumor activity and safety as a monotherapy, with 7 out of 14 patients with BRCA-mutated breast cancer showing confirmed responses, resulting in a response rate of 50%. Grade 3–4 adverse events included anemia (17 out of 71 patients; 24%) and thrombocytopenia (13 out of 71 patients; 18%) (12).

Talazoparib has been widely applied in clinical treatments for breast cancer, primarily as a monotherapy to assess efficacy (Table II). For instance, a phase II single-arm, open-label study (clinical trial no. NCT03499353) evaluated the efficacy of Talazoparib as a neoadjuvant therapy in patients with TNBC, and achieved a pathological complete response rate of 45.8% (95% CI, 29.4–63.2%) in the evaluable population, demonstrating considerable activity (101).

It is important to note that, when combining Talazoparib with other potent anticancer drugs, careful attention must be paid to dosing and administration sequence. Previous research has indicated a potential synergistic effect between antibody-drug conjugates (ADCs) and PARP inhibitors. ADCs can effectively increase DNA damage in tumor cells, and subsequent use of PARP inhibitors can further block DNA repair, leading to cancer cell apoptosis (102). However, simultaneous administration in clinical settings has shown significant toxicity, particularly myelosuppression. Sequential administration, however, creates a time window that allows PARP inhibitors to act more effectively within tumor cells without increasing toxicity (13).

Veliparib, a PARP inhibitor, has been evaluated in combination with other drugs in clinical trials for various cancer types. In the treatment of TNBC, its combination with cisplatin or carboplatin has shown good tolerability and response rates (14). In addition to its use in classic gynecological tumors such as breast and ovarian cancer, Veliparib has also been investigated in the treatment of non-small cell lung cancer, pancreatic cancer, prostate cancer and acute myeloid leukemia (103–106). Although Veliparib has not yet received broad clinical approval, its extensive research and application in various cancer types provides promising insights for future therapeutic strategies.

Recently developed in China, Fuzuloparib and Pamiparib are novel PARP inhibitors. In a phase I clinical trial (clinical trial no. NCT03945604) of Fuzuloparib for patients with recurrent or metastatic TNBC, 29 patients received camrelizumab (200 mg, every 2 weeks), Apatinib (375 or 500 mg, daily) and Fuzuloparib (starting dose of 100 mg, twice daily). In total, 2 patients (6.9%; 95% CI, 0.9–22.8) had an objective response, while the disease control rate was 62.1% (95% CI, 42.3–79.3). The median PFS was 5.2 months (95% CI, 3.6–7.3), while the 12-month OS rate was 64.2% (95% CI, 19.0–88.8), indicating controllable safety and preliminary antitumor activity (107). Similarly, another phase I trial (clinical trial no. NCT03075462) confirmed the acceptable safety of Fuzuloparib combined with Apatinib in patients with advanced ovarian cancer or TNBC (108).

In addition, Pamiparib in combination with the immune checkpoint inhibitor Tislelizumab demonstrated efficacy in a dose-escalation study for treating various advanced solid tumors (109). In monotherapy for patients with non-mucinous high-grade ovarian cancer and TNBC in China, the most common adverse effects were fatigue, nausea and hemoglobin reduction. Among all patients with TNBC who were evaluable under the Response Evaluation Criteria in Solid Tumors criteria (n=5), disease progression was reported, indicating the need for further evidence to support its efficacy in breast cancer (76).