PARP inhibitors are a targeted therapy used to treat certain cancers, including breast, ovarian, pancreatic, and prostate cancer, particularly in patients with BRCA1/2 mutations or other mutations that affect DNA repair systems in cells.
They block proteins called PARPs (or Poly (ADP-ribose) polymerases) that play an important role in the life of a cell. When a strand of the DNA double helix in a cell is broken or damaged, PARPs act as a repair crew to help fix the damaged site, allowing the cell to live. When another repair crew is compromised, cancer cells may depend on PARPs to remain alive, grow, and divide.
Drugs that inhibit or stop PARPs from doing their job can cause DNA damage to accumulate to the point where the cancer cell can no longer survive, making them a potential treatment option for some patients. They are particularly important for patients with inherited BRCA1/2 gene mutations or other gene mutations that also affect DNA repair pathways.
“If a tumor is deficient in one DNA repair pathway, like the BRCA pathway, it is now hyper-dependent on other DNA repair pathways,” explains Alan D’Andrea, MD, director of the Susan F. Smith Center for Women’s Cancers and the Center for DNA Damage and Repair at Dana-Farber. “If you can inhibit one of those other pathways, you’ll kill the cancer.”
Who can benefit from PARP inhibitors?
PARP inhibitors are a targeted therapy taken as a pill. They have been approved by the U.S. Food and Drug Administration for the treatment of:
- Breast cancer
- Ovarian, fallopian tube and primary peritoneal cancers
- Pancreatic cancer
- Prostate cancer
PARP inhibitors are typically used in patients with inherited BRCA1/2 gene mutations, though not exclusively. Scenarios in which PARP inhibitors are used for patients with inherited BRCA1/2 gene mutations include:
- Ovarian cancer: To treat recurrent cancer and as maintenance therapy after chemotherapy in patients with disease that is resistant to platinum chemotherapy.
- Pancreatic cancer: As maintenance therapy after chemotherapy.
- Prostate cancer: As treatment for castration-resistant prostate cancer.
- Breast cancer: To treat metastatic HER2-negative breast cancer and as maintenance therapy for early-stage high-risk HER2-negative breast cancer after treatment with chemotherapy and local treatment.
The PARP inhibitors that have been approved by the U.S. Food and Drug Administration include olaparib, rucaparib, niraparib, and talazoparib.
What are the side effects of PARP inhibitors?
The most common adverse side effect of PARP inhibitor treatment is anemia. Other side effects vary from one drug to another, but can include:
- Fatigue
- Nausea
- Diarrhea
- Headache
- Decreased appetite
- Dizziness
- Insomnia
- Skin rash
Your care team can work with you to help minimize these effects.
Do PARP inhibitors cause hair loss?
PARP inhibitors are classified as a form of targeted therapy and, unlike some types of chemotherapy, generally do not cause hair loss.
What is the current state of research into PARP inhibitors?
Over a decade has passed since the first PARP inhibitor was approved for the treatment of ovarian cancer in 2014. The clinical research behind that approval was led by Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber.
Research at Dana-Farber related to PARP inhibitors today has expanded to include a broad range of investigations to help determine if PARP inhibitors can benefit a wider range of patients and to uncover ways to improve outcomes for patients receiving PARP inhibitor therapy.
Exploring benefits in breast cancer
In 2024, Dana-Farber investigator Judy E. Garber, MD, MPH, chief of the Division of Cancer Genetics, reported findings that PARP inhibition shows long-term survival benefits for patients with high-risk, BRCA-positive breast cancer based on an analysis of data from OlympiA, a multicenter, double-blind study of 1,836 patients with BRCA-positive, HER2-negative breast cancer. These results also highlighted the safety of the PARP inhibitor olaparib.
Garber is now exploring the possibility of moving the use of PARP inhibitors to treat lower-risk BRCA-associated breast cancers and possibly even to explore the use of PARP inhibitors as part of an early interception strategy in patients with BRCA mutations who have not developed cancer but who have signs of cellular changes preceding cancer.
Understanding resistance to PARP inhibitors
One key challenge with PARP inhibitors is that cancers typically develop resistance to them. Dana-Farber investigator Dipanjan Chowdhury, PhD, is recently discovered that loss of a pathway involved in choosing a method for DNA repair can result in PARP inhibitor resistance. The findings could help clinicians guide the selection of treatments for patients.
Managing side effects with long term use
Patients with advanced ovarian cancer who are taking a PARP inhibitor as maintenance therapy might need to take the therapy for an extended period. The medicine can cause fatigue that may be difficult to manage. Dana-Farber clinical investigator Alexi Wright, MD, MPH, is exploring in a clinical trial whether a supportive intervention called REVITALIZE can help patients manage their side effects.
Clinical trials are also ongoing and planned to evaluate PARP inhibitors in combination with other treatments including radiation therapy and chemotherapy. More specialized PARP inhibitors that target specific forms of the PARP family of proteins are also under investigation.
About the Medical Reviewer
Dr. D’Andrea received his Doctor of Medicine from Harvard Medical School in 1983. He completed his residency at the Children’s Hospital of Philadelphia, and a fellowship in pediatric hematology-oncology at Dana-Farber Cancer Institute and Boston Children’s Hospital. He also completed a research fellowship at the Whitehead Institute of Biomedical Research at Massachusetts Institute of Technology, where he cloned the receptor for erythropoietin, the major hormone for blood production. Dr. D’Andrea joined the Dana-Farber faculty in 1990. He is currently the Fuller-American Cancer Society Professor of Radiation Oncology at Harvard Medical School, the Director of the Center for DNA Damage and Repair, and the Director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute.
Dr. D’Andrea is internationally known for his research in the area of DNA damage and DNA repair. His laboratory also investigates the pathogenesis of Fanconi Anemia, a human genetic disease characterized by a DNA repair defect, bone marrow failure, and cancer predisposition.
A recipient of numerous academic awards, Dr. D’Andrea is a former Stohlman Scholar of the Leukemia and Lymphoma Society, a Distinguished Clinical Investigator of the Doris Duke Charitable Trust, a recipient of the E. Mead Johnson Award from the Society for Pediatric Research, a recipient of the G.H.A. Clowes Memorial Award from the American Association for Cancer Research, a Fellow of the American Association for the Advancement of Science, a member of the American Association for Cancer Research Academy, the National Academy of Medicine, and the National Academy of Sciences.