PARP inhibitors: Overview and indications

PARP (poly ADP-ribose polymerase) are proteins that bind to broken strands of DNA and recruit other proteins to repair damaged DNA. There are multiple pathways (controlled by multiple genes) involved in DNA damage repair. The PARP family of proteins controls response to single-strand DNA breaks. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage.

In tumors that already have a DNA repair deficiency, due to pathogenic variants in genes involved in homologous recombination repair (HRR), such as BRCA1/2, disabling the PARP pathway further compromises the cell and leads to increased cell death (Coyne 2017). Other HRR genes include ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANC, PALB2, RAD51B, RAD51C, RAD51D , and RAD54L.

PARP inhibitors (e.g., olaparib, rucaparib, talazoparib) are most effective when alternative pathways are non-functional, as occurs when both copies of a gene are not working correctly. This is called bi-allelic loss and can be due to the presence of one germline and one somatic variant or two somatic variants. Currently, having a single variant in a HRR gene is sufficient to consider treatment with PARP inhibitors (PARPi).

The strongest evidence for the effectiveness of PARPi exists in patients with ovarian, breast, prostate, and pancreatic cancers that show evidence of deficiencies in HRR. The use of PARPi in other cancer types is being investigated.

FDA-APPROVED INDICATIONS

This resource summarizes the indications approved by the FDA. There may be additional indications supported by guidelines developed by organizations such as NCCN and ESMO that are not included in this resource.

PARPi treatments are approved to treat ovarian, primary peritoneum, fallopian tube, breast, pancreatic, and prostate cancers that have BRCA1/2 pathogenic variants or other markers of homologous recombination repair deficiency (HRD). They can also be used for advanced ovarian, primary peritoneum, and fallopian tube cancers that have previously responded to platinum-based therapy, regardless of the presence of genomic variants.

PARPi for maintenance therapy

Maintenance therapy is the use of a cancer drug in individuals who have complete or partial remission, with the goal of preventing recurrence or delaying growth of the tumor.

FDA-approved PARPi maintenance therapy indications

¹ g: pathogenic or suspected pathogenic germline variant

² s: pathogenic or suspected pathogenic somatic variant

³ HRD: homologous repair deficiency, defined by the companion diagnostic as the presence of a BRCA1/2 variant and/or genomic instability

PARPi for cancer treatment

PARPi have been approved to treat several different cancer types that have evidence of HRD based on the presence of a pathogenic variant in BRCA1/2 and/or evidence of genomic instability.

FDA-approved PARPi indications for cancer treatment

¹ g/s: germline or somatic variant

² g: germline variant

³ HRD: homologous repair deficiency

⁴ Homologous recombination repair (HRR) genes include BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L.

Companion diagnostics

Companion diagnostics are available, and in some cases required, to identify patients who may benefit from PARPi treatment, as specified in the tables above. If a patient is found to have a BRCA1/2 pathogenic variant through a genomic testing assay other than one of the currently approved companion diagnostic tests, the desired PARPi drug may still be covered by insurance. Contact the pharmaceutical company and patient’s insurance company to verify coverage for a specific patient. The FDA maintains a current list of approved companion diagnostic tests .

Patient Experiences and Side-Effects

PARP inhibitors are administered orally and may be taken at home continuously. The most common adverse effects observed with PARP inhibitor therapy include fatigue, anemia, nausea, neutropenia, thrombocytopenia, constipation, vomiting, diarrhea (Robson 2017; Litton 2018; LaFargue 2019). Most adverse events occur during the first cycles of treatment. In many cases, the side effects can be addressed through supportive care and dose reduction. Quality of life (QoL) studies in patients with ovarian cancer have shown no loss of QoL on two different PARPi therapies (Friedlander 2018; Oza 2018). In breast cancer, studies have showed higher overall and delays in deterioration of QoL scores in patients received PARPi compared to those receiving chemotherapy (Litton 2020).

Areas of Current Investigation

Although the relevance of PARPi is clear in some clinical situations, the underlying mechanisms of PARPi activity are not well understood, which limits the ability to identify potential targets for therapy and pathways to address acquired resistance. Some of the areas of current research include:

• Understanding PARPi resistance. A subset of patients on PARPi develop acquired resistance in their tumors over time. This resistance can develop in several ways, including acquiring resistance mutations. The most common of these resistance mutations restores the cell’s ability to repair DNA damage enough to allow for continued replication. These resistance mutations have been seen in patients with both germline and somatic BRCA1/2 mutated breast and ovarian cancers. Ongoing research is looking to understand resistance mechanisms and identify ways to overcome them. (Rose 2020)
• Combination treatments. Given high dosage requirements and the prevalence of acquired PARPi resistance, combination therapies are of significant interest to minimize dosage requirements and increase drug efficiency. (Rose 2020)
• PARPi effectiveness beyond label indications. Use of PARPi outside of the cancer types that have been approved for treatment has variable results. Ongoing research is assessing what factors influence the efficacy of PARPi, including cancer type, HRD status, HRR genes.

RESOURCES

• Publicly available knowledge bases contain information on the clinical impact of molecular biomarkers in cancer-related genes, associated treatments with levels of evidence, and available clinical trials. These knowledge bases include:
• Clinical Knowledge Base (CKB) from The Jackson Laboratory
• OncoKB from Memorial Sloan Kettering Cancer Center
• My Cancer Genome from Vanderbilt University
• Knowledge Base for Precision Oncology from MD Anderson Cancer Center
• The FDA maintains a current list of approved companion diagnostic tests .
• The non-profit, patient-focused organization FORCE offers several web resources on biomarker testing and targeted treatments geared towards patients including:
• DNA damage repair and cancer treatment
• PARP inhibitors
• Side effects of targeted therapy

Learn More

Exploring Cancer Biomarker Testing(CME | CNE ). Learn about benefits, limitations, and challenges of using cancer biomarker testing.

Interpreting Results from Somatic Cancer Panels (CME | CNE) . 15 to 30-minute case-based modules that let you learn how to find and use important information on somatic cancer testing panel reports.

Indications for Germline Testing in Cancer Patients. Identifies genetic red flags to inform personal and family history risk assessment and genomic tumor test results that are suggestive of a germline variant.

REFERENCES

AstraZeneca Pharmaceuticals LP. (2022). " Lynparza (olaparib) v. 10/22 [package insert]." Retrieved 4/27/23.

Clovis Oncology, Inc. (2022). " Rubraca (rucaparib) v.12/22 [package insert]." Retrieved 4/27/23.

Friedlander, M., et al. (2018). " Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised tria l." Lancet Oncol 19(8): 1126-1134.

GlaxoSmithKline (2022). " Zejula (niraparib) v. 12/22 [package insert]." Retrieved 4/26/23.

LaFargue, C. J., et al. (2019). " Exploring and comparing adverse events between PARP inhibitors. " Lancet Oncol 20(1): e15-e28.

Litton, J. K., et al. (2018). " Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. " N Engl J Med 379(8): 753-763.

Litton, J. K., et al. (2020). " Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. " Ann Oncol 31(11): 1526-1535.

National Comprehensive Cancer Network. (2022) NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer, v1.2023 . Accessed 4/27/23.

National Comprehensive Cancer Network. (2022) NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma, v2.2022 . Accessed 4/27/23.

National Comprehensive Cancer Network. (2022) NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, v1.2023 . Accessed 4/27/23.

National Comprehensive Cancer Network. (2023) NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, v4.2023.

Oza, A. M., et al. (2018). " Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial. " Lancet Oncol 19(8): 1117-1125.

Pfizer Labs. (2021). " Talzenna (talazoparib) v. 9/21 [package insert]." Retrieved 4/26/23.

Robson, M., et al. (2017). " Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. " N Engl J Med 377(6): 523-533.

Rose, M., et al. (2020). " PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. " Front Cell Dev Biol 8: 564601.

Revised 4/2023