PARP inhibitors are built on the idea of exploiting weaknesses in how tumor cells repair DNA. Among the different repair systems, PARP (poly ADP-ribose polymerase) enzymes are involved in fixing single-strand DNA breaks. When PARP detects damage, it binds to DNA and recruits other repair proteins to resolve it.
Blocking PARP prevents the repair of single-strand breaks, which can, in turn, cause double-strand breaks in DNA replication. This is usually handled by homologous recombination, a pathway that depends on proteins like BRCA1 and BRCA2.
This makes it an interesting mechanism in tumors where homologous recombination is already impaired, typically BRCA1- or BRCA2-mutant disease. There, PARP inhibition removes a remaining repair pathway, and DNA damage accumulates, eventually leading to cell death, referred to as synthetic lethality.
This was one of the first cases where a therapy was built around a specific weakness in DNA repair rather than a classical oncogenic target, with a relatively clear link between mechanism and patient selection.
The picture has since become more complex. PARP inhibitors not only block enzymatic activity; some also trap PARP on DNA, creating physical obstacles to replication.
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Where PARP inhibitors changed practice
The first therapeutic area where PARP inhibitors took hold was ovarian cancer, where they quickly became part of maintenance therapy after platinum-based chemotherapy. Early data with olaparib established this approach in BRCA-mutant advanced disease.
The strategy was later extended to a broader group of patients. Niraparib helped bring in the concept of homologous recombination deficiency (HRD), suggesting that benefits might go beyond BRCA mutations, although less consistently.
PARP inhibitors then moved into breast cancer therapies with olaparib and talazoparib approved in HER2-negative, BRCA-mutant disease. More recently, PARP inhibitors have also been used earlier in the treatment pathway, with olaparib showing benefit in high-risk early-stage disease.
In pancreatic cancer, olaparib is used as maintenance therapy in metastatic patients with BRCA mutations whose disease has not progressed on platinum chemotherapy.
More recently, prostate cancer has become another important area of development. Here, PARP inhibitors are used in patients with alterations in homologous recombination repair (HRR) genes, extending beyond BRCA in some cases, though with uneven benefit across genes.
At the same time, PARP inhibitors are increasingly combined with androgen receptor pathway inhibitors. The U.S. Food and Drug Administration (FDA) approved niraparib in combination with abiraterone and prednisone for metastatic castration-resistant prostate cancer. A similar approach has been taken with talazoparib combined with enzalutamide, also approved in HRR-altered metastatic disease.
PARP inhibition’s challenge: selecting the right patients
Tumors with BRCA1/2 alterations are where PARP inhibition remains the strongest, and also where the clinical signal has been most consistent. The industry tried to move beyond that group, but so far, that expansion has been uneven.
In ovarian cancer, the category of HRD-positive disease helped open PARP inhibitors to patients without a BRCA mutation, but it never became a yes-or-no marker. ESMO’s recommendations on HRD testing in ovarian cancer state that current assays are useful for estimating the likely magnitude of benefit, while also noting that better biomarkers are still needed. The same document notes that existing tests lack strong negative predictive value and do not fully capture the complex and dynamic nature of HRD.
As a consequence, in June 2025, the FDA narrowed Zejula’s first-line ovarian maintenance indication to HRD-positive tumors only. The updated label now defines that population as tumors associated with a deleterious or suspected deleterious BRCA mutation and/or genomic instability.
There is also a more technical problem in ovarian cancer: many HRD assays are based on genomic scars left by past repair defects, not on a live snapshot of what the tumor is doing now. A tumor can carry the historical marks of homologous recombination deficiency while no longer behaving like an HRD tumor at the time treatment starts.
The same issue appears in a slightly different form in prostate cancer, where PARP inhibitors moved into a broader HRR gene framework that includes genes such as ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, PALB2, and others. This sounds broad, but the benefit is not evenly distributed across that list. In the FDA summary for talazoparib plus enzalutamide, the exploratory analysis showed a much stronger effect in BRCA-mutated disease than in the non-BRCA HRR group. And in the FDA summary for niraparib plus abiraterone in metastatic castration-sensitive prostate cancer, the overall benefit in the HRR-mutated population was described as being driven primarily by the BRCA2-mutated subgroup.
PARP inhibitors may widen at the level of labels and trial design, but for now, the strongest and most reproducible signal still tends to sit with BRCA.
Limits of the class: resistance and toxicity
The first challenge with PARP inhibitors is resistance. A tumor that looked vulnerable at the start of treatment can change because of that same treatment and become less dependent on the repair weakness that made the therapy relevant initially.
The best-known resistance mechanism is BRCA reversion. Tumors can acquire secondary alterations that restore enough BRCA function to recover homologous recombination repair. Once that capacity returns, at least in part, PARP inhibition weakens.
Another route involves how tumor cells deal with stalled DNA replication. PARP inhibitors tend to create damage during this process, but some tumors adapt by preventing that damage from escalating. As a result, a tumor can remain BRCA-deficient on paper while becoming less sensitive in practice.
On the safety side, the main concern is hematologic toxicity, especially anemia, neutropenia, and thrombocytopenia. Myelosuppression is a recurring problem with PARP inhibition and with it comes dose interruption or reduction, monitoring, and sometimes transfusion support.
What comes next: improving on PARP inhibition
The first generation of drugs established the mechanism, but they also brought limitations. That has led to the development of more selective agents such as AstraZeneca’s saruparib (AZD5305), designed to inhibit PARP1 while sparing other PARP family members. The idea is to make PARP inhibitors easier to use, particularly in combination settings. AstraZeneca has already moved saruparib into multiple phase 3 trials across breast, prostate, and ovarian cancers.
The field is also moving toward combinations that build on the same DNA damage response logic. In prostate cancer, pairing PARP inhibitors with hormonal therapies has already become part of clinical practice, but the next wave is looking at how to extend or restore sensitivity more directly.
One approach is to target parallel DNA repair pathways, particularly through ATR inhibition. Several ATR inhibitors have entered clinical development, but development has been uneven, with programs evolving or being reprioritized, with compounds such as camonsertib, originally developed by Repare in collaboration with Roche. Roche has, however, dropped the candidate, and Repare will pursue development. AstraZeneca is also developing its own ATR inhibitor, ceralasertib.
A related idea is to exploit vulnerabilities that emerge once homologous recombination is impaired. Polθ inhibitors, such as Artios’ ART6043, are being developed on that basis, with early clinical data and regulatory designations in BRCA-mutated disease. The candidate received fast track designation from the FDA earlier this year.
Beyond new drugs and combinations, the question of patient selection remains. The next phase for the field may also be about identifying who is most likely to benefit, for how long, and whether PARP should be used alone or as part of a broader DNA damage response strategy.
