What Are PARP Inhibitors?

PARP stands for poly(ADP-ribose) polymerase. It is an enzyme that helps cells repair damaged DNA. A PARP inhibitor is a pill that blocks it.

Blocking DNA repair sounds like a strange goal. It works because of what these drugs are paired with. Every approved use demands a specific flaw in the cell's own repair kit.

One phrase runs through NCI's drug pages: homologous recombination repair, or HRR. That is how a cell makes a clean fix when both strands of DNA break. BRCA1 and BRCA2 are two of the genes that run it.

A tumor with a broken BRCA gene has already lost that route. Take PARP away too, and it has no way left to fix its DNA. A healthy cell still has the backup, because its BRCA genes work. That gap is the whole strategy.

Four PARP inhibitors are approved in the United States, each with its own list of uses.

• Olaparib, sold as Lynparza.
• Niraparib, sold as Zejula.
• Rucaparib, sold as Rubraca.
• Talazoparib, sold as Talzenna.

A common mistake is assuming that because one PARP inhibitor is approved for a cancer, all of them are. They are not. Match the drug to your exact situation.

Here the drug is usually not the treatment that shrinks the cancer. Chemotherapy does that. The PARP inhibitor is given afterward, to hold the response.

NCI lists olaparib for ovarian, fallopian tube, or primary peritoneal cancer. It is maintenance therapy given after platinum chemotherapy. It covers advanced disease with a germline or somatic BRCA1 or BRCA2 mutation. It is also approved with bevacizumab. That use covers advanced cancer with genomic instability, a BRCA mutation, or both. It is approved for recurrent disease as well.

Niraparib has two ovarian uses. The first is maintenance after first-line platinum chemotherapy. The cancer must be having a complete or partial response. The second is maintenance in recurrent cancer with a germline BRCA1 or BRCA2 mutation. Again, the cancer must be responding to platinum.

Rucaparib is approved as maintenance in adults whose ovarian cancer has come back. The cancer must be responding to platinum chemotherapy and must carry a BRCA1 or BRCA2 mutation.

Notice what all of these share. The cancer must first be responding to platinum. That response is itself a hint that DNA repair is broken.

Two drugs are approved here, and both require a germline BRCA1 or BRCA2 mutation and HER2-negative disease.

Olaparib is approved after surgery in two settings. One is high-risk early-stage disease treated with chemotherapy. The other is metastatic disease treated with chemotherapy.

The early-stage approval came on March 11, 2022. It rested on the OlympiA trial, which enrolled 1,836 patients. Events of invasive disease or death hit 106 patients on olaparib, or 12 percent. On placebo, the count was 178, or 20 percent. The hazard ratio was 0.58. The 95 percent confidence interval ran 0.46 to 0.74, with a p-value below 0.0001.

The amount used there is 300 mg by mouth, twice daily, for up to one year, with or without food. Read that as the trial and label figure. Your own prescription may say something smaller, because anaemia and low counts frequently prompt a reduction, and that sheet is the one to follow. Patients are chosen using an FDA-approved companion test.

Talazoparib is approved on its own for adults with HER2-negative metastatic breast cancer. They must carry a germline BRCA1 or BRCA2 mutation.

Prostate approvals widened the biomarker beyond BRCA alone.

Olaparib is approved on its own for metastatic castration-resistant prostate cancer. The tumor must carry germline or somatic mutations in HRR pathway genes, and the cancer must have progressed after enzalutamide or abiraterone. Olaparib is also approved with abiraterone plus prednisone or prednisolone. That combination is for BRCA1 or BRCA2 mutations.

Talazoparib is approved with enzalutamide for the same disease. Here the tumor must carry mutations in HRR pathway genes.

Rucaparib is approved for metastatic prostate cancer with a BRCA1 or BRCA2 mutation. It is for adults whose cancer has already been treated with antiandrogen therapy.

Castration-resistant means one thing. The cancer keeps growing even though testosterone has been driven very low.

One approval, and it is narrow. Olaparib is approved as maintenance for metastatic pancreatic cancer. The tumor must carry a germline BRCA1 or BRCA2 mutation. The disease must not have grown during first-line platinum chemotherapy.

Germline means the mutation is in every cell, inherited, and can be passed to children. Somatic means it arose in the tumor only.

Check your report for which one applies. Some approvals accept either. Olaparib in ovarian and prostate cancer is one example. Others demand germline. That includes both breast approvals and the pancreatic one.

A germline result is a family matter, not just a treatment matter. Ask for a genetic counseling referral for relatives.

OlympiA listed the side effects seen in at least 10 percent of patients. They were:

• Nausea, vomiting, and diarrhea.
• Fatigue, including asthenia, which means weakness.
• Anemia, meaning low red blood cells.
• Leukopenia and neutropenia, meaning low white blood cells.
• Headache and dizziness.
• Decreased appetite and dysgeusia, meaning a change in the sense of taste.
• Stomatitis, meaning sore mouth or mouth ulcers.

Anemia is the one that most often changes the plan. Expect regular blood counts. Also expect that a dose cut, not a stop, is the usual first move.

No PARP inhibitor is prescribed without a biomarker result. Before the visit, find out four things:

• Is BRCA1 or BRCA2 mutated? Is that mutation germline or somatic?
• For prostate cancer, is any other HRR pathway gene mutated?
• For ovarian cancer, does the tumor show genomic instability? It may be reported as homologous recombination deficiency.
• Is the test an FDA-approved companion test for the exact drug being considered?

Ask which sample was tested, blood or tumor tissue, and how old that sample is.

• Which PARP inhibitor is approved for my exact cancer and biomarker?
• Is this treatment or maintenance, and how long do I stay on it?
• What blood count schedule do you want, and at what level would you cut the dose?
• Is my mutation germline, and should my family be tested?
• What is the monthly cost with my insurance, and is there a patient assistance program?

These are pills taken at home, often for months. That puts the monitoring partly on you between blood tests.

• Call 911 or go to an emergency department if you have chest pain or tightness, sudden shortness of breath, a fast or pounding heartbeat, or you cough up blood.
• Call your care team the same day if you have a new or worsening cough, wheezing, or difficulty breathing, with or without a fever. Lung inflammation is uncommon but is taken seriously on these drugs.
• Contact your oncology team immediately, whatever the time, if you have a temperature of 100.4°F (38°C) or higher, chills, a sore throat, or pain when passing urine. These pills push white cells down, and CDC treats a fever on cancer drug treatment as a medical emergency, so use the out-of-hours number rather than waiting for the clinic to open. If you cannot get an answer quickly, go to an emergency department and tell them what you are taking.
• Call your care team the same day if you bruise or bleed unusually easily, or you see blood in your urine or stool.
• Call your care team within a day or two if you become unusually weak or very tired, look pale, or lose weight without trying. Anemia is the side effect that most often changes the dose.
• Call your care team within a day or two if one leg becomes painful, tender, red or swollen.

https://www.cancer.gov/about-cancer/treatment/drugs/olaparib

https://www.cancer.gov/about-cancer/treatment/drugs/niraparibtosylatemonohydrate

https://www.cancer.gov/about-cancer/treatment/drugs/rucaparibcamsylate

https://www.cancer.gov/about-cancer/treatment/drugs/talazoparibtosylate

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer

https://medlineplus.gov/druginfo/meds/a614060.html

https://medlineplus.gov/druginfo/meds/a617007.html

https://www.cancer.gov/about-cancer/treatment/side-effects/infection

https://www.cdc.gov/cancer-preventing-infections/patients/fever.html