PARP inhibitors
Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA).
The approved PARP inhibitors are olaparib, niraparib, rucaparib and talazoparib. They are standard as maintenance in BRCA/HRD ovarian cancer (SOLO-1, PRIMA), adjuvant in germline-BRCA HER2-negative breast cancer (OlympiA, with overall survival benefit), metastatic breast (OlympiAD, EMBRACA), HRR-mutant prostate (PROfound, PROpel, TALAPRO-2), and pancreatic maintenance (POLO). Resistance via BRCA reversion; PARP1-selective saruparib aims to widen the window.
How it works
Synthetic lethality: PARP trapping converts single-strand breaks into double-strand breaks that HR-deficient cells cannot repair.
- Oral, targeted to a germline-definable population
- Overall survival benefit in adjuvant setting
- Myelosuppression, MDS risk
- Reversion resistance
Billed as the first PARP inhibitor for triple-negative breast cancer, it failed its phase 3 in 2011. It turned out not to inhibit PARP at all.
Niraparib is a PARP inhibitor approved as maintenance for ovarian cancer regardless of BRCA status, and in prostate cancer with abiraterone.
Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.
A PARP inhibitor for BRCA-mutated ovarian and prostate cancer whose original maker went bankrupt; still available, with a narrowed label.
Talazoparib is the most potent PARP trapper, approved in BRCA breast cancer and with enzalutamide in prostate cancer.
Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.
Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.
Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.
Latest papers
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