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PARP Inhibitors in Ovarian Cancer: The Route to "Ithaca"
Stergios Boussios1,2, Afroditi Karathanasi3, Deirdre Cooke4
1Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK. stergiosboussios@gmail.com.
Abstract:
Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.
Insights
Poly (ADP-ribose) polymerase (PARP) inhibitors show efficacy in ovarian cancers with DNA repair defects. Identifying patients who benefit from PARP inhibitors using homologous recombination deficiency (HRD) scores remains a key challenge.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- High-grade serous ovarian cancer (HGSOC) exhibits genomic instability and homologous recombination (HR) DNA repair pathway defects.
- Poly (ADP-ribose) polymerase (PARP) inhibitors are a therapeutic class targeting tumors with HR repair deficiencies.
- PARP inhibitors have demonstrated efficacy in patients with BRCA1/2 mutations and those with other HR repair defects.
Purpose of the Study:
- To review current evidence on PARP inhibitors in ovarian cancer.
- To describe the mechanism of action of PARP inhibitors.
- To discuss challenges including toxicities and resistance evolution.
Main Methods:
- Literature review of studies on PARP inhibitors in ovarian cancer.
- Analysis of homologous recombination deficiency (HRD) scoring systems.
- Examination of patient selection strategies based on biomarkers.
Main Results:
- PARP inhibitors are effective in ovarian cancer patients with BRCA mutations and other HRD.
- Homologous recombination deficiency (HRD) scores are under development for patient selection.
- Patient selection for PARP inhibitor therapy based on HRD and other biomarkers is complex.
Conclusions:
- PARP inhibitors represent a significant advancement in ovarian cancer treatment for specific patient populations.
- Further research is needed to optimize patient selection and manage long-term toxicities and resistance.
- Companion diagnostics and biomarker assessments are crucial for guiding PARP inhibitor therapy.