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Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer
Andrisha-Jade Inderjeeth1, Monique Topp1, Elaine Sanij1,2,3,4
1Peter MacCallum Cancer Centre, Melbourne, VIC 3065, Australia.
Abstract:
Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.
Insights
Poly(ADP-ribose) polymerase inhibitors (PARPi) show significant benefit for men with metastatic castrate-resistant prostate cancer (mCRPC) who have homologous recombination repair (HRR) alterations. Their role is expanding to combination therapies for broader mCRPC treatment.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Approximately 25% of men with metastatic castrate-resistant prostate cancer (mCRPC) have homologous recombination repair (HRR) gene alterations.
- These HRR alterations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi).
- PARPi have demonstrated significant clinical benefit and survival advantage in mCRPC, particularly in patients with BRCA1/2 alterations.
Purpose of the Study:
- To review the development and expanding role of PARPi in prostate cancer.
- To explore biomarkers of response, the relationship between androgen receptor and PARP, and combination therapeutic strategies.
- To discuss future directions for PARPi in precision medicine for prostate cancer.
Main Methods:
- Literature review of studies on PARPi in prostate cancer.
- Analysis of clinical trial data and preclinical research.
- Synthesis of information on biomarkers, combination therapies, and future applications.
Main Results:
- PARPi are effective in mCRPC with HRR alterations due to synthetic lethality.
- The application of PARPi is expanding beyond HRR-deficient tumors.
- Combination strategies involving PARPi with other treatments show promise for enhanced benefits.
Conclusions:
- PARPi represent a key therapeutic strategy in mCRPC, especially for HRR-altered tumors.
- Combination therapies are emerging as a significant area of research for improving mCRPC outcomes.
- The future of PARPi in prostate cancer lies in personalized medicine approaches, guided by biomarkers and novel combinations.
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