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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.
Synthetic lethality: PARP trapping converts single-strand breaks into double-strand breaks that HR-deficient cells cannot repair.
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 a PARP inhibitor that traps PARP on DNA about 100 times more strongly than olaparib, which is why it works at a 1 mg daily dose. It is approved for germline BRCA-mutant HER2-negative breast cancer and, with enzalutamide, for HRR-mutant castration-resistant prostate cancer; anaemia is its dominant side effect.
Veliparib is a PARP inhibitor that AbbVie tested with chemotherapy in breast cancer. It added nothing to carboplatin before surgery (BrighTNess) and lengthened progression-free but not overall survival with carboplatin and paclitaxel in inherited BRCA advanced disease (BROCADE3), so it was never licensed.
Answers the two questions that hung over adjuvant olaparib, durability and late leukaemia, in its favour; the remaining question is whether carriers who also received pembrolizumab or capecitabine, whom the trial did not study, get the same benefit.
The third trial to show carboplatin's benefit persists beyond pathological complete response and the trial that closed the neoadjuvant PARP inhibitor route in unselected triple-negative disease; PARP inhibition survives only in germline BRCA carriers.
The survival result that moved adjuvant olaparib from a disease-free survival approval to an undisputed standard, and the reason germline testing at diagnosis of triple-negative breast cancer is now a treatment decision rather than a family history exercise.
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.
Sets the surgical and systemic rules for the one in nine to one in six triple-negative patients who carry a germline BRCA variant (11 to 17 percent by cohort); the adjuvant gap it named was filled by OlympiA the following year.
The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease.
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.
Query for this technology: (TITLE:"PARP inhibitor" OR ABSTRACT:"PARP inhibitor" OR TITLE:"PARP inhibitors" OR ABSTRACT:"PARP inhibitors" OR TITLE:"olaparib" OR ABSTRACT:"olaparib" OR TITLE:"niraparib" OR ABSTRACT:"niraparib"). Results are unfiltered search hits about PARP inhibitors, not a curated reading list.
Shares Ovarian Cancer Research Alliance (OCRA), A functional test for homologous recombination deficiency validated across laboratories, PRIMA / ENGOT-OV26, PAOLA-1 / ENGOT-ov25.
Shares STRIDE DNA break detection (intoDNA), A functional test for homologous recombination deficiency validated across laboratories, Isabelle Ray-Coquard, Mary-Claire King.
Shares Christopher Lord, Thomas Helleday, ATR and CHK1 inhibitors, Alan D. D'Andrea.
Shares ATR and CHK1 inhibitors, Alan D. D'Andrea, Radioligand plus DNA-repair inhibitor combinations, Enabling characteristic: genome instability and mutation.
Shares Jennifer K. Litton, Germline BRCA test → adjuvant PARP inhibitor, Mary-Claire King, TRITON3.
Shares D9319C00001- 1L OC Mono Global RCT, SOLO-1, PRIMA / ENGOT-OV26, PAOLA-1 / ENGOT-ov25.
Shares Roll Over StudY for Patients Who Have Completed a Previous Oncology Study With Olaparib, D9319C00001- 1L OC Mono Global RCT, Efficacy and Safety of Olaparib (MK-7339) in Participants With Previously Treated, Homologous Recombination Repair Mutation (HRRm) or Homologous Recombination Deficiency (HRD) Positive Advanced Cancer (MK-7339-002 / LYNK-002), FPI-2265 (225Ac-PSMA-I&T) and Olaparib for Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC).
Shares Mary-Claire King, Homologous recombination deficiency (HRD) in breast cancer, SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer, PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours.