Ovarian cancer is often diagnosed at advanced stages. Targeted therapies, which precisely attack cancer cells while minimizing harm to healthy tissue, represent a significant advancement. Among these, PARP inhibitors have emerged as a significant treatment option. These drugs specifically interfere with a cell’s ability to repair damaged DNA, offering a new approach to combat the disease.
Understanding PARP and DNA Repair
Poly (ADP-ribose) polymerase (PARP) is a natural protein in cells that repairs DNA. DNA damage occurs continuously, and PARP fixes single-strand breaks. This repair maintains genetic stability, allowing cells to grow and divide without harmful mutations.
Our bodies possess multiple pathways for DNA repair, acting as safeguards to ensure genomic integrity. When one repair pathway is compromised, other pathways can often compensate. For instance, the homologous recombination (HR) pathway is a high-fidelity mechanism for repairing more severe DNA damage, specifically double-strand breaks. Genes like BRCA1 and BRCA2 are integral components of this homologous recombination repair pathway.
Mutations in BRCA1 or BRCA2 genes can impair the HR pathway, making cells less effective at repairing double-strand DNA breaks. These genetic alterations can be inherited or acquired within tumor cells. When cells with these defects accumulate DNA damage, it can lead to uncontrolled cell growth and division, contributing to cancer development, including ovarian cancer. Approximately 15% to 20% of ovarian cancer cases involve either inherited or tumor-specific BRCA2 mutations.
How PARP Inhibitors Work
PARP inhibitors operate by disrupting the DNA repair capabilities of cancer cells, particularly those that already have deficiencies in other repair pathways, such as homologous recombination. These drugs prevent PARP from performing its normal repair work on single-strand DNA breaks. When PARP is inhibited, these single-strand breaks accumulate.
During cell replication, these unrepaired single-strand breaks can transform into more severe double-strand DNA breaks. In healthy cells with functional homologous recombination pathways, these double-strand breaks can still be repaired. However, in cancer cells that already have impaired homologous recombination, often due to mutations in genes like BRCA1 or BRCA2, they cannot effectively repair these new double-strand breaks.
This selective vulnerability of cancer cells is known as “synthetic lethality”. It means that while inhibiting PARP alone may not significantly harm healthy cells, and a BRCA mutation alone may not immediately kill a cancer cell, the combination of both defects leads to cancer cell death. By targeting PARP, these inhibitors overwhelm the cancer cell’s compromised DNA repair system, causing enough unrepaired damage to trigger cell death while largely sparing normal cells.
Using PARP Inhibitors in Ovarian Cancer
PARP inhibitors have transformed the treatment landscape for ovarian cancer, offering targeted options for various stages of the disease. They are used in several scenarios, including maintenance therapy after chemotherapy, and as treatment for recurrent or first-line disease. Their application often depends on specific genetic characteristics of the tumor.
Genetic testing for BRCA mutations and homologous recombination deficiency (HRD) status is important in determining eligibility for PARP inhibitors. Patients with BRCA1 or BRCA2 gene mutations, inherited or acquired within the tumor, respond well to these drugs due to their cancer cells’ DNA repair defect. HRD status identifies a broader group of tumors with similar DNA repair impairments, even without a BRCA mutation, which may also benefit from PARP inhibitor therapy.
Commonly used PARP inhibitors in ovarian cancer include olaparib, niraparib, and rucaparib. Olaparib was among the first approved PARP inhibitors for ovarian cancer, initially for recurrent disease with BRCA mutations, and later expanded for first-line maintenance therapy in combination with bevacizumab for HRD-positive cases. Niraparib is approved for maintenance therapy regardless of BRCA mutation or HRD status, offering a broader application. Rucaparib also has approvals for maintenance therapy in platinum-sensitive recurrent ovarian cancer, particularly for patients who have responded to prior platinum-based chemotherapy.
As maintenance therapy, PARP inhibitors aim to prevent or delay the return of cancer after patients have achieved a response to initial chemotherapy. Studies have shown that these drugs can significantly prolong progression-free survival, meaning the time patients live without their disease worsening. For instance, olaparib maintenance in patients with BRCA-mutated tumors has shown a median progression-free survival of 19.1 months compared to 5.5 months with placebo in some studies. While these drugs do not cure ovarian cancer, they can delay its progression, potentially improving quality of life and extending the time between chemotherapy treatments.
Managing Side Effects of PARP Inhibitors
Patients undergoing treatment with PARP inhibitors may experience various side effects, which can often be managed effectively to maintain quality of life. The most common adverse effects across all PARP inhibitors include fatigue, nausea, and changes in blood counts, such as anemia. These side effects generally stem from the way these drugs affect rapidly dividing cells, including healthy ones.
Fatigue is a common complaint, often mild to moderate. Nausea is also common, often occurring early in treatment. Healthcare teams may recommend antiemetic medications to help prevent or alleviate nausea. Adjusting meal timing, such as having light meals with an antiemetic before taking the medication, can also be helpful.
Hematologic side effects, particularly anemia (low red blood cell count), are frequently reported. Lowering the dose or temporarily stopping the medication might be necessary for more severe cases of anemia, or for other blood count issues like neutropenia (low white blood cell count) or thrombocytopenia (low platelet count). Regular blood tests are important to monitor these changes. Open communication with the healthcare team is important to address side effects promptly and ensure appropriate management strategies are put in place.