Poly (ADP-ribose) polymerase (PARP) inhibitors represent an advancement in cancer treatment, particularly as a targeted therapy. These medications work by interfering with the DNA repair mechanisms within cancer cells, offering a more precise approach compared to traditional chemotherapy. Their development marks a step in personalized medicine, especially for certain types of cancer. This class is prominent in managing specific malignancies, including ovarian cancer.
How PARP Inhibitors Work
PARP inhibitors target the poly(ADP-ribose) polymerase (PARP) enzymes, proteins involved in cellular DNA repair pathways. When DNA damage occurs, PARP1, a member of this family, binds to the damaged sites and initiates repair by adding poly(ADP-ribose) chains to proteins, which then recruit other repair machinery. This action repairs single-strand DNA breaks (SSBs), preventing them from becoming more severe double-strand breaks (DSBs).
PARP inhibitors block these enzymes, preventing SSB repair. Unrepaired SSBs accumulate, forming double-strand breaks during DNA replication. Cancer cells, particularly those with pre-existing defects in homologous recombination repair (HRR), become highly vulnerable to this accumulated damage.
The concept of “synthetic lethality” underlies the effectiveness of PARP inhibitors in these specific cancer cells. Synthetic lethality describes a situation where the disruption of one gene or pathway alone is tolerable for a cell, but the simultaneous disruption of two genes or pathways leads to cell death. Cells with mutations in BRCA1 or BRCA2 genes, which are involved in HRR, rely more heavily on PARP-mediated repair. When PARP is inhibited in these BRCA-mutated cells, they lose their primary and backup DNA repair mechanisms, leading to genomic instability and cell death. This selective targeting allows PARP inhibitors to preferentially harm cancer cells while largely sparing healthy cells that have intact DNA repair systems.
PARP Inhibitors for Ovarian Cancer
PARP inhibitors have become a standard treatment for advanced ovarian cancer. They are especially beneficial for individuals with mutations in the BRCA1 or BRCA2 genes, which are present in approximately 22% of ovarian cancer patients (15% inherited, 7% acquired).
The effectiveness of PARP inhibitors extends beyond BRCA mutations to include patients with homologous recombination deficiency (HRD), a broader term for impaired ability to repair double-strand DNA breaks. HRD testing helps identify a larger group of patients who may respond to these therapies. Approximately half of advanced ovarian cancers are associated with HRD.
PARP inhibitors are used in several settings for ovarian cancer. They are employed as maintenance therapy after platinum-based chemotherapy, both in the first-line setting and for recurrent disease. This maintenance approach aims to prolong progression-free survival (PFS). Studies have shown that PARP inhibitors can significantly extend PFS in patients with BRCA mutations or HRD.
For recurrent platinum-sensitive ovarian cancer, PARP inhibitors can also be used as a treatment for active disease, especially in patients with BRCA mutations. The goal is to control tumor growth and improve patient outcomes by exploiting the cancer cells’ inherent DNA repair vulnerabilities. The choice of PARP inhibitor and its specific application can vary depending on the patient’s genetic profile and prior treatment history, underscoring personalized treatment strategies.
Types of PARP Inhibitors
Several PARP inhibitor medications are approved for use in ovarian cancer treatment. Olaparib, Niraparib, and Rucaparib are among the most commonly utilized drugs in this class. Each of these agents has specific indications and characteristics that guide their application.
Olaparib
Olaparib was the first PARP inhibitor approved for ovarian cancer, initially for patients with germline BRCA mutations who had received multiple prior lines of chemotherapy. It is also approved as a first-line maintenance treatment for advanced ovarian cancer with BRCA1/2 mutations after a response to platinum-based chemotherapy, and for recurrent platinum-sensitive disease.
Niraparib
Niraparib is approved as a maintenance treatment for all patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have responded to platinum-based chemotherapy, regardless of BRCA mutation status. It also has an approval as a first-line maintenance therapy for a broader patient population.
Rucaparib
Rucaparib is indicated for the treatment of adult patients with germline or somatic BRCA mutation-associated ovarian cancer who have been treated with two or more prior lines of chemotherapy. It is also approved as a maintenance monotherapy for adult patients with recurrent ovarian cancer who have achieved a complete or partial response to platinum-based chemotherapy.
Patient Experience and Side Effects
Patients experience various side effects, which are generally manageable. The most common adverse events include fatigue, nausea, anemia, abdominal pain, and decreased appetite. These side effects often appear early in the treatment course and may improve over time.
Fatigue is a common side effect, reported in up to 60-70% of patients, though it is often low-grade. Nausea is also frequently observed, affecting over 75% of patients, but severe nausea (grade 3 or 4) is uncommon. Gastrointestinal issues such as abdominal pain, constipation, or diarrhea are also possible. Eating smaller, more frequent meals and staying hydrated can help manage digestive symptoms.
Hematologic side effects, including anemia (low red blood cell count), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count), are common with all PARP inhibitors. Anemia is particularly prevalent, occurring in 20-25% of patients, and can cause symptoms like tiredness, weakness, or shortness of breath. Regular blood tests are performed to monitor these cell counts.
Managing these side effects often involves proactive strategies and close communication with the healthcare team. Dose adjustments, such as reducing the dosage or temporarily pausing treatment, can help alleviate severe symptoms without necessarily compromising treatment effectiveness. Supportive care, including anti-nausea medications, iron supplements for anemia, or other red blood cell stimulating factors, may also be prescribed. Patients are encouraged to promptly report any side effects to their healthcare providers to ensure appropriate and timely management.