Frequently Asked Questions: PARP Inhibition Therapy
Q: What is PARP inhibition therapy?
PARP (poly ADP-ribose polymerase) are proteins that bind to broken strands of DNA, and recruit other proteins to repair damaged DNA. PARP inhibition therapy (PARPi) targets tumors that already have a DNA repair deficiency (e.g., pathogenic variants (mutations) in BRCA1/2). By disabling the PARP mechanism for DNA repair, treatment further compromises the cell and leads to increased cell death.
Q: Are there FDA-approved indications or guidelines for cancer treatment with PARPi?
PARPi can be used to treat certain advanced ovarian, primary peritoneum, fallopian tube, breast, pancreatic, and prostate cancers that have BRCA1/2 and other homologous recombinant repair (HRR) gene pathogenic variants. It can also be used for maintenance therapy in advanced ovarian, primary peritoneum, and fallopian tube cancers that have previously responded to platinum-based therapy, regardless of the presence of genomic variants. PARPi can also be considered for maintenance therapy in metastatic pancreatic adenocarcinomas with germline BRCA1/2 variants in certain clinical situations. Current NCCN guidelines include these recommendations. (see more details in the table below).
Q. What FDA-approved drugs are available?
|Drug||Cancer site||Genomic variants1||Eligibility||Goal|
|Olaparib||Ovary, primary peritoneum or fallopian tube||Germline BRCA1/2||Advanced cancer, treated with 3 or more previous lines of chemotherapy||treatment|
|Germline or somatic BRCA1/2||Advanced cancer, complete or partial response to first-line platinum-based chemotherapy||maintenance|
|n/a||Recurrent cancer, complete or partial response to platinum-based chemotherapy|
|Breast||Germline BRCA1/2||HER2- metastatic cancer, previously treated with chemo||treatment|
|HER2+ cancer, previously treated with endocrine therapy or not appropriate for endocrine therapy|
|Pancreatic||Germline BRCA1/2||Metastatic pancreatic adenocarcinoma, no progression for 16+ weeks on first-line platinum-based chemotherapy||maintenance|
|Prostate, metastatic castration-resistant||Germline or somatic homologous recombinant repair (HRR) gene variant3||Progressed on hormone therapy (enzalutamide or abiraterone)||treatment|
|Olaparib + bevacizumab||Ovary, primary peritoneum or fallopian tube||Germline or somatic BRCA1/2 OR genomic instability2
||Advanced cancer, complete or partial response to first-line platinum-based chemotherapy||maintenance|
|Rucaparib|| Ovary, primary peritoneum or fallopian tube
|| Germline or somatic BRCA1/2
||Advanced cancer, treated with 2 or more previous lines of chemotherapy||treatment|
|Advanced cancer, complete or partial response to first-line platinum-based chemotherapy||maintenance|
|n/a||Recurrent cancer, complete or partial response to platinum-based chemotherapy|
|Prostate, metastatic castration-resistant||Germline or somatic BRCA1/2
||Previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy||treatment|
|Talazoparib||Breast||Germline BRCA1/2||HER2- locally advanced or metastatic cancer||treatment|
|Niraparib||Ovary, primary peritoneum or fallopian tube||Somatic BRCA1/2||Advanced cancer, treated with 3 or more previous lines of chemotherapy||treatment|
|Germline or somatic BRCA 1/2 OR genomic instability2||Advanced cancer, treated with 3 or more previous lines of chemotherapy + progression > 6 months after response to last platinum-based chemotherapy|
|n/a||Recurrent cancer, complete or partial response to platinum-based chemotherapy||maintenance|
1Genomic variants indicate those that are predicted to be pathogenic or likely pathogenic and, therefore have an impact on gene function.
2 Genomic instability is determined by the genomic instability score calculated on an approved companion diagnostic test that assesses for genomic changes that indicate possible tumor response to PARPi therapy.
3 Homologous recombination repair genes include ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FACL, PALB2, RAD51, and RAD54.
Q. Are there other indications for PARPi therapy?
There is growing evidence that other tumor types with BRCA1/2 mutations may respond to PARP inhibition, and that mutations in other homologous recombinant repair (HRR) genes (e.g., ATM, BRIP1, CHK1, CHK2, PALB2, RAD51) may also render tumor cells sensitive to PARP inhibition (Lord 2016).
There are clinical trials assessing the effectiveness of PARP inhibitors in different clinical situations. PARPi therapy clinical trial topics include:
- Response to PARPi monotherapy or combination therapy in a range of solid tumors with variants in a range of DNA repair genes.
- Efficacy of new, non-FDA-approved PARP inhibitors in advanced solid tumors.
- Role of platinum-resistant disease in combination with other agents
- Efficacy of currently available PARP inhibitors
- Tolerability and efficacy of FDA-approved PARP inhibitors
PARP inhibition often comes up in Molecular Tumor Board discussions as a potential therapy to explore in patients with DNA damage repair gene mutations through clinical trials or off-label.
Q: What have patient experiences been with PARP inhibition therapy so far?
A: PARP inhibitors are administered orally and may be taken at home continuously. The most common adverse effects observed with PARP inhibitor therapy are anemia, neutropenia, thrombocytopenia, nausea and fatigue (Robson 2017; Litton 2018). If a patient does experience intolerable side effects, it is recommended to either decrease the dose of the PARP inhibitor or interrupt therapy until symptoms improve. It is usually not necessary to discontinue treatment entirely due to adverse effects (Moore 2018).
Currently, data is limited about the long-term effects of administration of PARP inhibitors. Limitations for long term use may include the development of bone marrow disorders, drug resistance, and cytotoxicity.
- Facing our Risk of Cancer Empowered (FORCE) offers a comprehensive PARPi therapy web article: Companion diagnostic testing
- 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. A number of organizations have developed knowledge bases, including the following.
- Clinical Knowledge Base (CKB) from The Jackson Laboratory
- My Cancer Genome from Vanderbilt University
- Knowledge Base for Precision Oncology from MD Anderson Cancer Center
- National Cancer Institute offers a list of clinical trials using Veliparib in advanced solid tumors
Astrazeneca Pharms. Lynparza® (olaparib) highlights of prescribing information – Suppl 14. Published 5/19/20. Accessed 6/1/20.
Clovis Oncology Inc. Rubraca® (rucaparib) highlights of prescribing information – Suppl 4. Revised 5/20. Accessed 6/1/20.
Dziadkowiec KN, Gasiorowska E, Nowak-Markwitz E, and Jankowska A. PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Menopause Rev. 2016; 15(4):215-219.
Hopkins TA, Ainsworth WB, Ellis PA. PARP1 Trapping by PARP Inhibitors drives cytotoxicity in both cancer cells and healthy bone marrow. Mol Cancer Res. 2019; 17:409-419.
Litton J et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-63.
Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 2016;16:110-20.
Lui Y, Meng J, Wang G. Risk of selected gastrointestinal toxicities associated with poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of ovarian cancer: a meta-analysis of published trials. Drug Des Devel Ther. 2018; 12:3013-3019.
McCann KE and Hurvitz SA. Advances in the use of PARP inhibitor therapy for breast cancer. Drugs in Context. 2018; 7:212540.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, v4.2020. Published 5/8/20. Accessed 6/1/20.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer, v1.2020. Published 3/11/20. Accessed 6/1/20.
Pfizer Inc. Talzenna® (talazoparib) highlights of prescribing information. Published 3/20. Accessed 6/1/20.
Robson M et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523-33.
Tesaro Inc. Zejula® (niraparib) highlights of prescribing information – Suppl 17. Published 4/29/20. Accessed 6/1/20.