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This sponsored educational video and transcript from Dr. Tanya Dorff, the Division Chief of the Genitourinary Disease Program at City of Hope in Duarte, CA, discusses the emerging role of PARP inhibitors in treating metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination repair (HRR) mutations. The content presents evidence on the prevalence of actionable genomic alterations, particularly BRCA1/2 mutations, and highlights the clinical significance of genetic testing to identify candidates for targeted therapy.
Key Clinical Considerations
- Approximately 14-16% of prostate cancer patients have actionable genomic alterations, with HRR deficiencies present in 20-30% of mCRPC cases, significantly higher than in localized disease
- HRR mutations (BRCA1, BRCA2, ATM) correlate with more aggressive disease and poorer prognosis, with BRCA-mutated cancers twice as likely to be associated with aggressive phenotypes
- Despite NCCN recommendations for germline and somatic testing in mCRPC patients, implementation remains suboptimal with fewer than 30% of metastatic patients receiving NGS testing
- Several PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib) have received FDA approval for mCRPC patients with specific HRR mutations
- Treatment intensification remains a challenge, with real-world data showing more than half of treated patients receive only one line of therapy
Clinical Practice Impact
- Patient Identification: Implement systematic genetic testing protocols for all advanced prostate cancer patients to identify HRR mutations that could indicate PARP inhibitor eligibility
- Treatment Selection: Consider PARP inhibitors as monotherapy or in combination with androgen receptor pathway inhibitors based on specific mutation profiles identified through testing
- Equity Considerations: Address the disparity in testing rates between Black and White patients (10.5% vs 16.3% for germline testing) to ensure equal access to targeted therapies
- Treatment Sequencing: Recognize that patients with HRR mutations may have inferior responses to conventional first-line androgen receptor-directed therapies, potentially warranting earlier consideration of PARP inhibitors
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