Olaparib
Olaparib
The first PARP inhibitor exploited a concept called synthetic lethality to fight cancer.
Killing cancer by breaking its last line of DNA defence.
Key Facts
- 1The first-in-class PARP inhibitor approved for cancer treatment
- 2Exploits "synthetic lethality": two non-lethal defects that become lethal together
- 3Generated ~$3.7 billion in annual sales across four cancer types
- 4Specifically targets tumours with BRCA1 or BRCA2 mutations
- 5Validated a new paradigm: targeting DNA repair as a cancer therapy strategy
The Problem
Why This Molecule Was Needed
BRCA1 and BRCA2 are tumour suppressor genes essential for homologous recombination repair (HRR), one of the cell's most important DNA repair pathways. When both copies are mutated (as occurs in many hereditary breast, ovarian, prostate, and pancreatic cancers), the cell loses its ability to accurately repair double-strand DNA breaks. Platinum-based chemotherapy was historically the only option, creating DNA crosslinks these repair-deficient cells cannot fix, but it caused severe side effects (kidney damage, neuropathy, bone marrow suppression) and resistance inevitably developed.
Scientists turned to a concept called synthetic lethality: loss of either gene alone is survivable, but loss of both is lethal. If BRCA-mutant cancer cells had already lost HRR, knocking out a second repair pathway should kill them selectively. The target they found was PARP1, an enzyme critical for repairing single-strand DNA breaks. Blocking PARP in BRCA-mutant cells would leave no functioning repair mechanisms, leading to catastrophic DNA damage and cell death, while normal cells with intact BRCA would survive because they still have HRR as a backup.
The Discovery
How It Happened
Synthetic lethality proven in the lab
Two landmark papers (by Farmer et al. and Bryant et al.) independently show that BRCA-deficient cells are over 1000-fold more sensitive to PARP inhibition than BRCA-proficient cells.
KuDOS Pharmaceuticals discovers olaparib
KuDOS Pharmaceuticals (later acquired by AstraZeneca) identifies olaparib, a phthalazinone-based PARP inhibitor that binds in the nicotinamide-binding pocket of PARP1 with an IC50 of 5 nM.
Proof of concept in BRCA patients
A Phase I trial shows clinical benefit in 63% of BRCA-carrier ovarian cancer patients, with some responses lasting over a year, translating synthetic lethality from theory to clinical reality.
First PARP inhibitor approval
The EMA approves olaparib for BRCA-mutated advanced ovarian cancer, the first approved PARP inhibitor and the first therapy based on synthetic lethality.
Expanding across cancer types
Olaparib gains approvals for breast cancer (2018), pancreatic cancer (2019), and prostate cancer (2020). The SOLO-1 trial shows that maintenance olaparib in newly diagnosed BRCA-mutant ovarian cancer improves 5-year progression-free survival from ~21% to ~48%.
The Molecule
Up Close
Tap any region or group card to explore key structural features.
The Takeaway
Synthetic lethality turns a cancer's weakness into its downfall
Olaparib represents a shift from poisoning all dividing cells to exploiting a cancer's specific DNA repair vulnerability. By understanding the repair network, scientists made one defect (BRCA loss) lethal by adding a second (PARP inhibition), while normal cells with intact BRCA survive. The concept has since expanded beyond BRCA mutations to any tumour with homologous recombination deficiency.
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