PARP inhibitors remain strongest in BRCA-mutant tumors as labels narrow

PARP inhibitors are built on the idea of exploiting weaknesses in how tumor cells repair DNA, and they became part of maintenance therapy after platinum-based chemotherapy in ovarian cancer. 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.

Among the different repair systems, PARP enzymes are involved in fixing single-strand DNA breaks. 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. In tumors where homologous recombination is already impaired, typically BRCA1- or BRCA2-mutant disease, PARP inhibition removes a remaining repair pathway, and DNA damage accumulates, eventually leading to cell death, referred to as synthetic lethality.

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, 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 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 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.

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. 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.