What are PARP inhibitors?

PARP inhibitors are a type of targeted therapy commonly used to treat breast cancer and ovarian cancer, among others. They target PARP, or poly (ADP-ribose) polymerase, which is a protein in cells that helps repair damaged DNA.

DNA damage is a normal part of a cell’s life cycle, and it doesn’t prevent cells from growing and dividing, as long as they can repair the damage. “PARP inhibitors are a class of drug that interferes with a cell’s ability to repair its DNA,” says Jennifer Litton, M.D., vice president of Clinical Research.

How PARP inhibitors work

PARP inhibitors are especially effective at treating cancers with gene mutations that negatively affect DNA repair, such as BRCA gene mutations. Because the cancer cells have these defects, they depend more on PARP to help repair damaged DNA.

“When a cancer cell already has impaired damage repair, such as in patients with a BRCA mutation, the cancer cell cannot fix itself,” Litton says. “PARP inhibitors block the cancer cell from repairing its damaged DNA, so it cannot divide to make more cancer cells and dies.”

Potential side effects of PARP inhibitors

Targeted therapy with PARP inhibitors is taken orally as a pill and has been shown to extend progression-free survival of patients with BRCA-mutated cancers. “Unfortunately, every therapy we have has some side effects,” says Litton.

She adds that PARP inhibitors’ side effects can include:

• low red blood cells (anemia)
• low white blood cells
• low platelets
• fatigue
• nausea
• headaches

“Some PARP inhibitors also cause hair loss,” she adds. These side effects are not usually debilitating and can be treated.

When PARP inhibitors are used

“PARP inhibitors can be used when there is an inherited defect in the cells’ DNA repair or if that defect is in the tumor cell itself. Currently, PARP inhibitors have been used to treat certain breast, prostate and gynecologic cancers,” explains Litton.

Examples of PARP inhibitors include:

• olaparib
• talazoparib
• rucaparib
• niraparib

PARP inhibitors can also be used in combination with other treatments like immunotherapy or chemotherapy. Chemotherapy works by damaging the DNA of cancer cells, leading to the death of those cancer cells. Because PARP inhibitors make it even harder for the cancer cells to repair their DNA, taking a PARP inhibitor while undergoing chemotherapy can help make the cancer cells more susceptible to chemotherapy. PARP inhibitors used in combination with both immunotherapy and chemotherapy have been shown to reduce the risk of disease progression in patients with advanced or recurrent endometrial cancer.

The future of PARP inhibitors

While PARP inhibitors are effective, they have some limitations, including the types of cancer they can treat and the development of resistance to them. But, Litton notes, “Multiple PARP inhibitor combination studies are underway with the hopes that they may be used for a wider variety of tumors, different defects in DNA repair mechanisms, to combat resistance or prolong response.”

A frequent problem with PARP inhibitors is that patients may eventually develop resistance to them, making them less effective in the long run. At a basic science level, researchers are studying patient samples to understand how cancer cells acquire resistance to PARP inhibitors and to find new biomarkers that we can use to predict if a patient is more likely to develop resistance.

Researchers are also looking at other targeted therapies that could be used in combination with PARP inhibitors to help overcome resistance and improve treatment response. One targeted therapy that shows promising results when used with PARP inhibitors is a PRMT inhibitor. PRMT, or protein arginine methyltransferase, is another protein in cells that interacts with DNA. A combination treatment with both has shown promise in in vitro and in vivo studies and is currently being researched further.

According to Litton, “We are also interested in newer members of this family to see if they can work with fewer side effects or with more responses.” First-generation PARP inhibitors such as niraparib, developed by Philip Jones, Ph.D., vice president of Research Strategy, Transformation and Operations, block both PARP1 and PARP2, two different types of the PARP protein. Next-generation PARP inhibitors focus on PARP1, making them potentially safer. PETRA, a first-in-human Phase I/IIa trial is looking at one such next-generation PARP inhibitor, saruparib, in patients with metastatic prostate cancer.

Researchers from MD Anderson are presenting on PETRA results and other advances in PARP inhibitors at the 2024 American Association for Cancer Research (AACR) Annual Meeting. “These advancements will help solidify PARP inhibitors as a foundational class of cancer drugs,” says Litton.

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