PARP inhibitors: Overview and indications

Summary: This resource discusses FDA-approved indications for PARP inhibitor (PARPi) for maintenance therapy and cancer treatment.

By Clinical Education at JAX | March 2024

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 disabling the PARP pathway further compromises the cell and leads to increased cell death (Coyne 2017). 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 bi-allelic loss can be due to the presence of one germline and one somatic variant or two somatic variants.

The strongest evidence for the effectiveness of PARPi exists in patients with ovarian, breast, prostate, and pancreatic cancers that show evidence of deficiencies in BRCA1/2. Determining other biomarkers of DNA repair deficiency and, therefore, predictive of response to PARP inhibitors is an active area of clinical research in a range of cancer types. These studies include assessing the impact pathogenic variants in other HRR genes and in markers of genomic instability, including loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) scores. HRR genes, other than BRCA1/2, include ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANC, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

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 in 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. PARPi are currently FDA-approved for maintenance therapy in ovarian and pancreatic cancers that meet specific criteria.

FDA-approved PARPi maintenance therapy indications

Eligibility Niraparib Olaparib Olaparib + bevacizumab Rucaparib
OVARIAN: Epithelial ovarian, primary peritoneum or fallopian tube
Advanced cancer, complete or partial response to first-line platinum-based chemotherapy Biomarker independent  g/s BRCA1/2 HRD+  
Recurrent cancer, complete or partial response to platinum-based chemotherapy  g BRCA1/2  g/s BRCA1/2    
Recurrent cancer, complete or partial response to platinum-based chemotherapy in the second line or later        g/s BRCA1/2
 PANCREATIC
 Metastatic, no progression for more than 16 weeks of a first-line platinum-based chemotherapy    g/s BRCA1/2  

g: pathogenic or suspected pathogenic germline variant

s: pathogenic or suspected pathogenic somatic variant

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 or other HRR genes. PARPi are currently FDA-approved for treatment in breast and prostate cancers that meet specific criteria.

FDA-approved PARPi indications for cancer treatment

Eligibility Olaparib Olaparib + abiraterone + prednisone Rucaparib Talazoparib Talazoparib + enzalutamide
BREAST
HER2-negative locally advanced or metastatic breast cancer         g BRCA1/2  
HER2- metastatic cancer, previously treated with chemotherapy and, if indicated, endocrine therapy   g BRCA1/2        
HER2- high risk early breast cancer previously treated with chemotherapy  g BRCA1/2        
PROSTATE
Metastatic castration-resistant    g/s BRCA1/2      HRR gene variant
Metastatic castration-resistant, progression previously on enzalutamide or abiraterone  g/s HRR gene variant        
Metastatic castration-resistant, previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy      g/s BRCA1/2    

g/s: germline or somatic variant

HRR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D andRAD54L.

Companion diagnostics

Companion diagnostics are available, and in some cases required, to prescribe PARPi on-label. If a patient is found to have a BRCA1/2 pathogenic variant through an 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 . The table below lists the current approved companion diagnostics with the associated drug and indication.

FDA-approved companion diagnostics

   BRCA Analysis CDx FoundationOne CDx FoundationOne Liquid CDx Myriad MyChoice CDx
Biomarkers Assessed

 BRCA1, BRCA2 BRCA1, BRCA2, HRR genes BRCA1, BRCA2, ATM HRD
DRUG CANCER        
Olaparib Ovarian X X    
Pancreatic X      
Breast X      
Prostate X X X  
Olaparib + bevacizumab Ovarian X X   X
Olaparib + abiraterone + prednisone Prostate     X  
Rucparib Prostate     X  
Talazoparib Breast X      

RESOURCES

Learn More

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

Interpreting Cancer Biomarker Testing – When is Additional Testing Needed? (CME | CNE).Learn when additional cancer biomarker testing is indicated for further evaluation of genome-informed therapy.

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.

Homologous Recombination Deficiency (HRD) Testing: FAQs. Provides an overview of biomarkers included in HRD testing.

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.

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

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.

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

Disclaimer

All information in this resource is provided for educational purposes only.