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What are PARP inhibitors and how do they work?

PARP inhibitors are a class of targeted cancer drug that work by taking advantage of the impaired DNA repair mechanisms in some cancer cells, leading to selective cancer cell death.

Poly-ADP ribose polymerase (PARP) is an enzyme that is involved in repairing single-strand DNA breaks. PARP inhibitors trap PARP at sites of DNA damage, leading to an accumulation of unrepaired single strand breaks that result in the collapse of replication forks during DNA replication, thus leading to double-strand breaks (DSBs).

In cancer cells that are deficient in homologous recombination (HR), these DSBs cannot be repaired, resulting in high levels of genetic instability and cell death. Cells with constitutional (germline) and/or somatic (tumour) variants in BRCA1 and BRCA2, or in other genes associated with HR repair, may be HR-deficient.

The selective toxicity that PARP inhibitors exhibit in HR-deficient cancer cells is termed synthetic lethality: when a defect in one gene or pathway is compatible with cell viability, but when combined with a defect in another gene or pathway leads to cell death.

PARP inhibitors in ovarian cancer

PARP inhibitors are particularly effective against BRCA-deficient cancer cells, and thus were initially reserved for ovarian cancers associated with constitutional (germline) or somatic (tumour) BRCA1/BRCA2 variants. Their use has now been expanded to include patients without such variants, following evidence of benefit to all patients within clinical trials.

  • NICE 2019 guidelines recommend olaparib for use within the Cancer Drugs Fund for the maintenance treatment of BRCA1/BRCA2 mutation-positive, advanced, high-grade epithelial ovarian cancer that has responded to first-line platinum-based chemotherapy. (See SOLO1 trial.)
  • Patients without evidence of a BRCA1/BRCA2 variant are eligible for first-line maintenance treatment with other PARP inhibitors. (See PRIMA and PAOLA-1 trials.)
  • NICE 2021 guidelines recommend olaparib in combination with bevacizumab for use within the Cancer Drugs Fund for patients with HR-deficient tumours as an option for maintenance treatment when there has been a complete or partial response after first-line platinum-based chemotherapy plus bevacizumab.
  • If not received in the first-line maintenance setting, patients can receive PARP inhibitors in the relapsed disease maintenance setting if they have responded to platinum chemotherapy, regardless of BRCA1/BRCA2 or HR deficiency. (See NOVA and ARIEL3 trials.)

PARP inhibitors in breast cancer

PARP inhibitors have been licensed in Europe for the second-line treatment of metastatic HER2-negative breast cancer in patients with a constitutional BRCA1 or BRCA2 variant, but have not yet been approved by NICE for use in the NHS. (See OlympiAD and EMBRACA clinical trials.)

PARP inhibitors are being studied in HER2-negative breast cancer in multiple clinical trials, including in the adjuvant setting for patients with a constitutional BRCA1 or BRCA2 variant with a high risk of relapsed disease. (OlympiAD study, in progress.)

PARP inhibitors in other cancers

Selected PARP inhibitors are approved by the US Food and Drug Administration and the European Medicines Agency for use in HR-deficient (somatic (tumour) and constitutional (germline)) metastatic castration-resistant prostate cancer (see TOPARP-B and PROfound studies), but are not currently recommended by NICE.

Other tumour types seen in patients with constitutional BRCA1 or BRCA2 variants include pancreatic cancer and melanoma. Treatment with PARP inhibitors within the treatment and maintenance settings is currently limited to clinical trials.

Resources

For clinicians

References:

Tagged: Therapies, Cancer

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2023
  • Authors: Dr Helen Hockings
  • Reviewers: Dr Amy Frost, Dr Ramsay Bowden, Dr Ellen Copson, Professor Kate Tatton Brown