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Therapies

PARP inhibitors

PARP inhibitors are routinely used in the treatment of ovarian cancer and selected breast and prostate cancers. Clinical trials are ongoing to determine efficacy in other tumour types. The choice of which PARP inhibitor to use may be affected by constitutional (germline) and/or somatic (tumour) BRCA1 and BRCA2 variant status.

What are PARP inhibitors and how do they work?

Poly-ADP ribose polymerase (PARP) inhibitors are a class of targeted cancer drug that works by taking advantage of the impaired DNA repair mechanisms in some cancer cells, leading to selective cancer cell death.

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.

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

The selective toxicity that PARP inhibitors exhibit in HR-deficient cancer cells is termed synthetic lethality. The term describes the phenomenon in which 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 currently available include olaparib, rucaparib and niraparib, all of which are oral medications. Reported toxicities include:

  • increased risk of infection, anaemia and bleeding as a result of myelosuppression;
  • tiredness;
  • nausea and/or vomiting;
  • mouth soreness and taste changes;
  • diarrhoea;
  • headache;
  • fatigue;
  • dizziness; and
  • alteration in liver and renal function.

PARP inhibitors in ovarian cancer

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

  • NICE guidelines recommend olaparib for the maintenance treatment of BRCA1 and 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 or 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.
  • Patients who have not received PARP inhibitors in the first-line maintenance setting can receive them in the relapsed disease maintenance setting if their cancer has demonstrated response to platinum-based chemotherapy, regardless of BRCA1 or BRCA2 status or HR deficiency (see NOVA and ARIEL3 trials).

Created in and exported from biorender.com.

Figure 1: Tumours that are BRCA-deficient are not able to repair double-stranded DNA breaks ordinarily repaired by homologous recombination. PARP is used for repair of single-stranded DNA breaks. When PARP inhibitors are used, cells that are BRCA-deficient cannot effectively repair single- or double-stranded DNA damage, such that the damage overwhelms the cell, leading to cell death. Tumours that are not BRCA-deficient can repair double-stranded DNA damage, such that the cells are not reliant on PARP and are therefore not prone to PARP-inhibitor induced cell death.

PARP inhibitors in breast cancer

PARP inhibitors have been licensed in Europe for the second-line treatment of metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer in patients with a constitutional (germline) BRCA1 or BRCA2 variant on the basis of the OlympiAD and EMBRACA clinical trials. These trials demonstrated improvements in progression-free survival with olaparib and talazoparib respectively compared to standard chemotherapy treatments. NICE has recently issued guidance recommending talazoparib for the treatment of HER2-negative, locally advanced or metastatic breast cancer in those with constitutional (germline) BRCA1 or BRCA2 variants if they have had an anthracycline or a taxane, or both (along with endocrine therapy if they have hormone receptor (HR)-positive breast cancer).

The OlympiAD study reported a significant improvement in both invasive disease-free survival and overall survival associated with the use of the PARP inhibitor olaparib as an adjuvant therapy after standard neoadjuvant or adjuvant chemotherapy for HER2-negative early breast cancer in patients with a constitutional (germline) BRCA1 or BRCA2 variant. This treatment option was approved by NICE in April 2023 and is now available via the Cancer Drugs Fund. Other breast cancer clinical trials such as PARTNER are currently investigating the use of PARP inhibitors in the neoadjuvant treatment setting.

PARP inhibitors in other cancers

The PARP inhibitor olaparib has been approved by NICE for use in metastatic castration-resistant prostate cancer associated with constitutional (germline) or somatic (tumour) BRCA1 and BRCA2 variants. This recommendation is based on the results of the TOPARP-B and PROfound clinical trials.

Olaparib has been licensed by the European Medicines Authority for maintenance treatment of adult patients with constitutional (germline) BRCA1 or BRCA2 variants who have metastatic adenocarcinoma of the pancreas and have not progressed after over 16 weeks of platinum treatment within a first-line chemotherapy regimen (based on the phase three POLO trial results). However, it has not been approved by NICE.

Use of PARP inhibitors in other tumour types is currently limited to clinical trials.

Resources

For clinicians

References:

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  • Last reviewed: 15/04/2024
  • Next review due: 15/04/2025
  • Authors: Dr Helen Hockings
  • Reviewers: Dr Ramsay Bowden, Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh, Professor Kate Tatton-Brown