Parp InhibitorsEdit

Parp inhibitors are a class of targeted cancer therapies that disrupt the ability of certain tumor cells to repair their DNA. By blocking the activity of poly(ADP-ribose) polymerase enzymes, these drugs exploit a vulnerability present in cancers with defective DNA repair pathways. The result can be selective killing of cancer cells while limiting damage to most normal cells. The concept of exploiting DNA repair weaknesses through PARP inhibition has become a cornerstone of precision oncology, particularly in tumors driven by mutations in BRCA1 or BRCA2 and other homologous recombination genes. For readers who want the molecular underpinnings, see poly(ADP-ribose) polymerase and BRCA1/BRCA2.

PARP inhibitors entered clinical practice after demonstrating meaningful benefits in several cancers, most notably in ovarian cancer, but also in certain breast, pancreatic, and prostate cancers. They are approved in various regimens as maintenance therapy, monotherapy, or in combination with other treatments, depending on tumor type and molecular profile. The drugs commonly discussed in this class include olaparib, niraparib, rucaparib, and talazoparib, each with its own regulatory history, dosing, and safety profile.

Mechanism of action

PARP inhibitors block the catalytic activity of PARP enzymes and can trap PARP on DNA at sites of single-strand breaks. When replication forks encounter these trapped complexes, they can collapse and give rise to double-strand breaks. In cells with intact homologous recombination repair, these breaks can be fixed; in cells with defects in BRCA1/2 or related pathways, repair is impaired, leading to cell death. This principle—synthetic lethality—underpins the therapeutic rationale for PARP inhibitors in cancers with BRCA mutations or homologous recombination deficiency. For background on the DNA repair machinery, see Homologous recombination and DNA damage repair.

Key terms and concepts to explore include synthetic lethality and the role of BRCA1/2 in maintaining genome integrity. The pharmacologic action of PARP inhibitors intersects with the broader field of targeted cancer therapy and the evolving understanding of how tumor genomes shape treatment responses.

Approved indications and representative agents

PARP inhibitors have been approved for a range of indications, with approvals evolving as new trial data emerge. The major agents and their common clinical roles include:

olaparib: Approved for ovarian cancer with BRCA mutations and other homologous recombination deficiencies, in maintenance settings after response to platinum therapy, and for certain breast, pancreatic, and prostate cancers with relevant mutations. See also the concept of maintenance therapy maintenance therapy.
niraparib: Widely used as maintenance therapy in ovarian cancer regardless of BRCA mutation status in some regimens, and also approved for other settings when applicable mutations or biomarker status are present.
rucaparib: Used in ovarian cancer with related mutations and in other contexts depending on prior treatments and biomarker status.
talazoparib: Particularly relevant for BRCA-mutated, HER2-negative breast cancer, with ongoing research in other tumor types.

These agents are used across disease lines in settings defined by mutation status, histology, prior therapies, and regulatory approvals. See also germline mutation and somatic mutation to distinguish inherited versus tumor-acquired alterations.

Clinical use in specific cancers

Ovarian cancer: The most established role for PARP inhibitors is in epithelial ovarian cancer, especially in tumors harboring BRCA mutations or other homologous recombination deficiencies. They are employed as maintenance therapy after a positive response to platinum-based chemotherapy and, in some cases, as part of a treatment regimen for relapsed disease. The utility of this approach depends in part on tumor HRD status and prior lines of therapy. See also BRCA1 and BRCA2.
Breast cancer: For breast cancer, PARP inhibitors are approved for patients with germline BRCA mutations and certain HRD-positive tumors, particularly in the metastatic setting or after neoadjuvant/adjuvant strategies in specific circumstances. The landscape includes distinctions between subtypes such as hormone receptor–positive and triple-negative disease, with ongoing trials refining which patients benefit most.
Pancreatic cancer: In metastatic pancreatic ductal adenocarcinoma, PARP inhibitors are approved for tumors with germline BRCA mutations or other qualifying alterations, offering a targeted option where standard therapies have limited long-term benefit. See also pancreatic cancer.
Prostate cancer: For metastatic castration-resistant prostate cancer with BRCA mutations or other homologous recombination gene alterations, PARP inhibitors have shown activity and are part of the evolving treatment paradigm in biomarker-selected patients. See also prostate cancer.

Clinical practice emphasizes careful patient selection based on molecular testing, including assessment of BRCA1/BRCA2 status and broader HRD assessments. Some regulatory approvals are contingent on specific line of therapy, prior responses to platinum chemotherapy, or performance status, illustrating the importance of individualized treatment planning. See also germline mutation and somatic mutation.

Safety, adverse effects, and monitoring

PARP inhibitors are generally well tolerated relative to cytotoxic chemotherapy, but they carry distinctive risks that require monitoring. Common adverse effects include anemia, thrombocytopenia, nausea, fatigue, and mild to moderate effects on the gastrointestinal and hematologic systems. Less commonly, patients may experience head or back pain, hypertension, or transaminitis. Rare but important risks include myelodysplastic syndrome/acute myeloid leukemia with prolonged exposure in some settings and potential secondary malignancies, highlighting the need for ongoing surveillance and risk-benefit assessment.

Monitoring typically involves periodic blood counts, liver function tests, and evaluation of symptoms. Drug interactions (for example, with agents that affect drug metabolism) may necessitate dose adjustments. Clinicians weigh the magnitude of anticancer benefit against the risk of adverse effects to guide duration of therapy and sequencing with other treatments. See also myelodysplastic syndrome and chronic myeloid leukemia for related hematologic considerations.

Resistance and future directions

Tumors can develop resistance to PARP inhibitors through several mechanisms, such as restoration of BRCA1/2 function, restoration of homologous recombination, upregulation of drug efflux pumps, or stabilization of replication forks. Such resistance can limit duration of response and influence subsequent treatment choices. Research is increasingly focused on combination strategies (for example, pairing PARP inhibitors with DNA-damaging chemotherapy, anti-angiogenic agents, or immunotherapies) and on refining patient selection through more precise HRD testing and biomarker development. See also replication fork protection and drug resistance.

Controversies and debates (neutral overview)

As with many targeted therapies, the use of PARP inhibitors raises questions about optimal patient selection, broad versus narrow indications, and cost considerations. Debates center on:

Biomarker strategy: How best to define HRD status and who should receive PARP inhibitors beyond BRCA mutations.
Maintenance versus treatment: When to use PARP inhibitors as maintenance therapy versus earlier or later lines of therapy, balancing progression-free survival gains with quality of life.
Cost and access: High drug prices and payer restrictions can affect availability, particularly in settings with limited healthcare resources.
Long-term outcomes: The durability of benefit and overall survival impact in various tumor types remain subjects of ongoing investigation.

See also cost-effectiveness and biomarker testing for related discussions.