PARP (poly-ADP-ribose polymerase) inhibitors have become a cornerstone treatment for ovarian cancer, particularly for patients with BRCA mutations and homologous recombination deficiency (HRD).
PARP inhibitors work by blocking an enzyme involved in DNA repair.
Cancer cells with defective DNA repair mechanisms, like those with BRCA mutations, become particularly vulnerable when PARP is inhibited, leading to cell death through synthetic lethality.
PARP enzymes help repair single-strand DNA breaks.
In cancers with BRCA1/2 mutations or homologous recombination deficiency (HRD), cells already have impaired DNA repair mechanisms.
High grade serous ovarian cancer frequently have underlying homologous recombination deficiency which occurs in approximately 50% of the tumors.
Approximately 22% of the tumors harbor BRCA mutations either germline or somatic.
PARP inhibitors are primarily used as maintenance therapy after chemotherapy, both in first-line treatment and for recurrent disease.
The utilization of PARP inhibitors as first-line maintenance therapy for advanced ovarian cancer has increased with PARPS being approved for recurrent platinum sensitive maintenance therapy, and upfront maintenance setting for platinum sensitive high-grade cancers.
PARPs is approval have been withdrawn in the recurrent setting, including patients with heavily treated recurrent BRCA or HRD ovarian cancer and non-BRCA or BRCA wild, platinum sensitive disease as maintenance as these have been associated with risk of AML or myelodysplastic syndrome.
The main PARP inhibitors approved for ovarian cancer include: Olaparib (Lynparza) – the first FDA-approved PARP inhibitor for ovarian cancer Niraparib (Zejula) Rucaparib (Rubraca)
While initially developed for patients with BRCA mutations, PARP inhibitors have shown benefit in broader patient populations: high-grade serous histology, in which BRCA mutations and homologous recombination deficiency are most common .
Clinical Indications
Maintenance Therapy After response to platinum-based chemotherapy BRCA-mutated or HRD-positive tumors HRD-negative tumors: Niraparib is still approved; others less effective
Treatment Settings: Recurrent ovarian cancer with BRCA mutation PARP inhibitors can be used as monotherapy, especially if platinum-sensitive
BRCA & HRD Testing are mandatory before starting to determine: Germline or somatic BRCA1/2 mutations HRD status
Common Side Effects Fatigue Nausea/vomiting Anemia Thrombocytopenia Rare: Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
Poly (ADP-ribose) polymerase (PARP) inhibitors play a central role in the treatment of ovarian cancer as maintenance therapy following a response to platinum-based chemotherapy, particularly in high-grade serous or endometrioid ovarian cancer.
The greatest benefit is observed in patients with BRCA1/2 mutations or homologous recombination deficiency (HRD), but PARP inhibitors are also approved for use regardless of BRCA or HRD status in certain settings.
PARP inhibitors (olaparib, niraparib, rucaparib) are recommended as maintenance therapy for patients with newly diagnosed or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved a complete or partial response to platinum-based chemotherapy.
The magnitude of benefit in progression-free survival (PFS) is highest in BRCA-mutated tumors followed by HRD-positive tumors, and is more modest in BRCA wild-type/HRD-negative tumors.
Olaparib is typically dosed at 300 mg orally twice daily for up to 2 years, and niraparib at 200–300 mg once daily for up to 3 years, as maintenance therapy.
Combination maintenance with olaparib and bevacizumab is approved for HRD-positive tumors, including those with BRCA mutations.
PARP inhibitors are also approved as active therapy for patients with BRCA-mutated ovarian cancer who have received multiple prior lines of therapy.
Toxicities include hematologic adverse events :anemia, neutropenia, thrombocytopenia), fatigue, and gastrointestinal symptoms.
The risk-benefit profile should be considered, especially in patients without BRCA mutations or HRD.