PARP Inhibitors

PARP inhibitors block poly(ADP-ribose) polymerase, which repairs single-strand DNA breaks, and trap PARP on DNA. Cells with defective homologous recombination (BRCA1, BRCA2 or related mutations) cannot repair the resulting double-strand breaks and die: a synthetic lethal effect. They are used as oral maintenance after platinum response in ovarian cancer, and in breast, prostate and pancreatic cancer with homologous recombination deficiency.

Classification. Olaparib, niraparib, rucaparib, talazoparib.

Pharmacokinetics. Olaparib and rucaparib are metabolised by CYP3A4 and CYP2D6; niraparib is cleared by carboxylesterase; talazoparib is renally cleared.

• Olaparib 300 mg tablets twice daily.
• Niraparib 300 mg once daily (200 mg once daily if weight is under 77 kg or platelets under 150 x 10^9/L).
• Rucaparib 600 mg twice daily.
• Talazoparib 1 mg once daily (breast cancer).

Differences. Niraparib causes more thrombocytopenia and hypertension; olaparib causes anaemia and nausea; rucaparib raises creatinine and liver enzymes.

• Ovarian cancer (high-grade, platinum-sensitive): maintenance after response to platinum chemotherapy; olaparib for 2 years (longer if still benefiting), niraparib until progression, with or without bevacizumab.
• Breast cancer (germline BRCA-mutated, HER2-negative): olaparib or talazoparib in metastatic disease; adjuvant olaparib 1 year in high-risk disease.
• Prostate cancer: olaparib or niraparib with an androgen receptor inhibitor or abiraterone in castration-resistant disease with BRCA or homologous recombination mutations.
• Pancreatic cancer (germline BRCA-mutated): maintenance olaparib after platinum response.
• Testing: germline or somatic BRCA and homologous recombination deficiency testing before starting; genetic counselling for relatives.
• Dose reductions: olaparib in steps to 250 mg then 200 mg twice daily; niraparib to 200 then 100 mg once daily.

Selection. Use after response to platinum chemotherapy; cost and genomic testing limit access in East Africa.

Contraindications. Pregnancy; hypersensitivity; active myelodysplastic syndrome or acute myeloid leukaemia.

Adverse effects. Anaemia (most common), neutropenia and thrombocytopenia, nausea, vomiting, fatigue, diarrhoea, headache, hypertension (niraparib), pneumonitis (rare), venous thromboembolism, and myelodysplastic syndrome or acute myeloid leukaemia (about 1 percent).

Interactions. Avoid strong and moderate CYP3A4 inhibitors; if unavoidable reduce olaparib to 100 mg twice daily (strong) or 150 mg twice daily (moderate); avoid strong inducers (rifampicin, phenytoin, carbamazepine, St John's wort); ritonavir-boosted regimens raise exposure.

Special groups.

• Pregnancy: contraindicated; effective contraception during treatment and for 6 months after the last dose.
• Breastfeeding: avoid during treatment and for 1 month after.
• Children: not used.
• Older adults: more anaemia; dose reduce early.
• Kidney impairment: olaparib 200 mg twice daily at creatinine clearance 31 to 50 mL/min; avoid under 30 mL/min.
• Liver impairment: caution in moderate disease; avoid in severe.

Monitoring. Full blood count weekly for the first month, then monthly for 11 months, then periodically; blood pressure with niraparib; liver and renal function; transfusion for anaemia.

Referral and escalation. Persistent cytopenia lasting 4 weeks after interruption needs bone marrow assessment for myelodysplastic syndrome.