For those with hereditary breast cancer (BC) tumors caused by germline BRCA1/2 (gBRCA) mutations, administration of the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors has resulted in improved outcomes. Of the four PARP inhibitors currently on the market (niraparib, olaparib, rucaparib, and talazoparib), only olaparib and talazoparib are approved for use in BRCA-mutated BC.

A recent narrative review discussed the mechanism of action of PARP inhibitors, the clinical evidence for the use of PARP inhibitors in advanced and early-stage setting BC, and future therapeutic strategies. The review also clarified the role of PARP inhibitors in the treatment landscape of patients with BC.

DNA breaks are continuously taking place, with tens of thousands occurring on a daily basis. DNA damage repair (DDR) pathways are involved in repairing DNA damage that can result in single-strand or double-strand DNA breaks, base damage, bulky adducts, crosslinks, or replication lesions. BRCA1/2 genes are involved in homologous recombination repair (HRR), which is a DNA repair pathway that enables cells to access and copy intact DNA sequence information to be used to repair DNA breaks affecting both strands of the double helix and interstrand crosslinks.

Deficiency in the HRR pathway is associated with the development of BC. Both BRCA1 and BRCA2 proteins facilitate HRR, which promotes genomic stability and suppresses tumor formation. A single copy of either the BRCA1 or BRCA2 gene is sufficient to repair DNA breaks, but a double hit is needed to prevent sloppy back-up repair of the HRR pathway. In patients with germline BRCA (gBRCA) alterations, these mutations impact the DNA repair process, resulting in the formation of unstable structural rearrangements. Repair of the double-stranded DNA break results in the more error-prone nonhomologous end-joining repair pathway, which links the break ends without the need for a homologous or intact DNA sequence template.

PARP proteins (PARP1 and PARP2) are nuclear enzymes that are involved in DDR processes, with PARP1’s activity primarily focused on DNA repair processes. When either a single- or double-strand DNA break occurs, PARP binds to the break, recruits DDR components that work to stabilize the replication fork (i.e., the Y-shaped area where the DNA double helix splits into two strands), and repairs the DNA break. In patients with gBRCA mutations, inhibiting PARP results in the impairment of alternative DDR pathways that are trying to repair the DNA damage, leading to cell death. This process of simultaneous impairment of alternative DDR pathways is termed synthetic lethality. PARP inhibitors are thought to act by competing with nicotinamide adenine dinucleotide (a coenzyme needed for energy metabolism) binding (called catalytic inhibition) or by causing PARP trapping (i.e., the generation of PARP-DNA complexes that block the replication fork, leading to its collapse).

However, over time, resistance to PARP inhibitors develops. Mechanisms of PARP inhibitor resistance include restoration of HRR activity, upregulated signaling pathways, replication-fork stabilization, decreased PARP1 trapping, and upregulation of adenosine triphosphate–binding cassette transporters.

While the use of olaparib has improved progression-free survival the objective response rate (ORR) in gBRCA1/2-associated BC, it has not been shown to increase overall survival (OS) in patients with advanced disease. Talazoparib also did not improve OS in this group. However, both olaparib and talazoparib improved health-related quality of life and delayed time to deterioration.

The use of PARP inhibitors in combination with chemotherapy is currently being explored. However, there is concern that combination therapy may increase PARP inhibitor toxicity, which includes hematologic (anemia, neutropenia), gastrointestinal (nausea and vomiting), and constitutional (fatigue) adverse effects. It is unclear whether PARP inhibitors play a role in homologous recombination deficiency (HRD) or “BRCAness,” which refers to a tumor phenotype without gBRCA1/2 alterations. An epigenetic change that can result in HRD is the methylation of the BRCA1 gene promoter, which leads to HRR misfunctioning.

Use of PARP inhibitors in early-stage gBRCA1/2 variants in triple-negative BC (TNBC), which is a more aggressive form of BC, is being investigated. Talazoparib has been associated with the development of a pathologic complete response (pCR) in more than one-half of patients, which is similar to the pCR achieved with anthracycline-taxane–based neoadjuvant regimens. Niraparib was associated with a 40% pCR in patients with estrogen receptor–positive BC and TNBC. Coadministration of PARP inhibitors and chemotherapy is also being explored in the early disease setting. Beneficial effects on reducing recurrence and mortality were seen in the early setting with olaparib administered to patients with high-risk human epidermal growth factor receptor 2 BC who harbored gBRCA1/2 variants after chemotherapy.

Future therapeutic strategies are geared toward combating the resistance that develops to PARP inhibitors. These strategies include the use of novel combination regimens (niraparib plus pembrolizumab, olaparib plus durvalimab, atezolizumab plus olaparib, antibody drug conjugates carrying a topoisomerase inhibitor [e.g., sacituzumab govitecan or trastuzumab deruxtecan plus a PARP inhibitor]; the use of ataxia telangiectasia and Rad3-related and WEE1 kinases or bromodomain and extraterminal protein inhibitors and PARP inhibitors); and a new generation PARP inhibitors including PARP1-specific inhibitors, since PARP1 is responsible for the synthetic lethality effects whereas PARP2 is associated with the development of hematologic toxicity. Other agents under development include dual inhibitors of PARP1 and intracellular molecules, such as histone deacetylases, DNA topoisomerases, or P13K pathway effectors and PARP1 degraders.

As the landscape for integration of PARP inhibitors into the management of BC keeps evolving to optimize treatment of their patients with BC, pharmacists should be aware of the appropriate use of these agents, ongoing research involving novel drug combinations designed to reduce drug resistance, studies exploring expanded use of these pharmaceuticals, and need for monitoring the safety and efficacy of PARP inhibitors.

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