What are olaparib's mechanisms in ovarian cancer therapy?

Olaparib is a PARP1/2 inhibitor. Its anti-tumor effects in ovarian cancer mainly come from exploiting synthetic lethality in homologous recombination–deficient (HRD) tumors (e.g., BRCA1/2-mutant cancers). Key mechanisms:

- Inhibition of PARP catalytic activity (base excision repair): PARP1/2 normally detect single-strand breaks (SSBs) and help repair them via base excision repair. Olaparib blocks this activity, leading to accumulation of SSBs that can collapse replication forks into double-strand breaks (DSBs).

- PARP‑DNA trapping: Olaparib traps PARP enzymes on DNA, creating PARP–DNA complexes. These stalled forks progress to more damage and replication fork collapse, increasing the load of DSBs.

- Synthetic lethality in HR-deficient cells: BRCA1/2 mutations or other HR repairs defects prevent efficient repair of DSBs by homologous recombination. The DSBs accumulated due to PARP inhibition/trapping are lethal to these cells, while normal cells (with intact HR) can survive.

- Enhancement in HRD tumors: The effect is strongest in tumors with HR defects, including BRCA-mutated ovarian cancers, but can also occur in tumors with other HRD characteristics (“BRCAness”).

- Clinical context: This mechanism underpins olaparib’s use as maintenance therapy after platinum response in BRCA-mutated or HRD ovarian cancer, and as treatment for recurrent ovarian cancer with BRCA mutation or HRD.

Additional notes:
- Resistance can develop (e.g., BRCA reversion mutations, restoration of replication fork protection, PARP1 mutations, drug efflux), which can restore DNA repair or reduce drug engagement.
- Olaparib’s PARP-trapping potency is a notable aspect of its mechanism and contributes to its efficacy, but also to some toxicity.

If you want, I can tailor this to BRCA-mutant vs. BRCA-wild-type but HRD ovarian cancers or discuss how this informs combination strategies.