PARP inhibitors

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 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 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.)

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.

For clinicians

• NICE: Consultation on olaparib for previously treated BRCA-mutation positive hormone-relapsed metastatic prostate cancer
• NICE: Guidance on olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy
• NICE: Guidance on olaparib with bevacizumab for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer

References:

• Ashworth A. ‘A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair’. Journal of Clinical Oncology 2008: volume 26, issue 22, pages 3,785–90. doi: 10.1200/JCO.2008.16.0812
• Coleman RL, Oza AM, Lorusso D and others. ‘Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial’. The Lancet 2017: volume 390, issue 10,106, pages 1,949-61. doi: 10.1016/S0140-6736(17)32440-6
• Franzese E, Centonze S, Diana A and others. ‘PARP inhibitors in ovarian cancer’. Cancer Treatment Reviews 2019: volume 73, pages 1-9. doi: 10.1016/j.ctrv.2018.12.002
• Golan T, Hammel P, Reni M and others. ‘Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer’. The New England Journal of Medicine 2019: volume 381, issue 4, pages 317-27. doi: 10.1056/NEJMoa1903387
• González-Martín A, Pothuri B, Vergote I and others. ‘Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer’. The New England Journal of Medicine 2019: volume 381, issue 25, pages 2,391-402. doi: 10.1056/NEJMoa1910962
• Konstantinopoulos PA, Ceccaldi R, Shapiro GI and others. ‘Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer’. Cancer Discovery 2015: volume 5, issue 11, pages 1,137–54. doi: 10.1158/2159-8290.CD-15-0714
• Litton JK, Rugo HS, Ettl J and others. ‘Talazoparib in patients with advanced breast cancer and a germline BRCA mutation’. The New England Journal of Medicine 2018: volume 379, issue 8, pages 753-63. doi: 10.1056/NEJMoa1802905
• Mateo J, Porta N, Bianchini D and others. ‘Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial’. The Lancet Oncology 2020: volume 21, issue 1, pages 162-174. doi: 10.1016/S1470-2045(19)30684-9
• Mirza MR, Monk BJ, Herrstedt J and others. ‘Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer’. The New England Journal of Medicine 2016: volume 375, issue 22, pages 2,154-64. doi: 10.1056/NEJMoa1611310
• Moore K, Colombo N, Scambia G and others. ‘Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer’. The New England Journal of Medicine 2018: volume 379, issue 26 pages 2,495-05. doi: 10.1056/NEJMoa1810858
• Ray-Coquard I, Pautier P, Pignata S and others. ‘Olaparib plus bevacizumab as first-line maintenance in ovarian cancer’. The New England Journal of Medicine 2019: volume 381, issue 25, pages 2,416-28. doi: 10.1056/NEJMoa1911361
• Robson M, Im SA, Senkus E and others. ‘Olaparib for metastatic breast cancer in patients with a germline BRCA mutation’. The New England Journal of Medicine 2017: volume 377, issue 6, pages 523-33. doi: 10.1056/NEJMoa1706450
• Sandhu, SK, Hussain, M, Mateo, J and others. ‘PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations’. Annals of Oncology 2019: volume 30, supplement 9, pages IX188-IX189. doi: 10.1093/annonc/mdz446.007