What is the role of Homologous Recombination Repair (HRR) gene mutations in the treatment of metastatic Castration-Sensitive Prostate Cancer (CSPC)?

Role of Homologous Recombination Repair (HRR) Gene Mutations in Metastatic CSPC Treatment

HRR gene mutations in metastatic Castration-Sensitive Prostate Cancer (CSPC) primarily serve as predictive biomarkers for potential PARP inhibitor therapy in later disease stages, though currently their clinical utility is limited to the metastatic Castration-Resistant Prostate Cancer (mCRPC) setting where specific mutations (particularly BRCA1/2) confer treatment benefits with FDA-approved PARP inhibitors. 1

Prevalence and Types of HRR Mutations

• Approximately 25% of men with metastatic prostate cancer harbor alterations in HRR genes 2
• Key HRR genes include:
  • BRCA1, BRCA2 (strongest evidence for treatment benefit)
  • ATM, PALB2, FANCA, RAD51D, CHEK2, and others 1
• These mutations may be either germline (inherited) or somatic (acquired)

Current Clinical Implications in CSPC

While HRR mutations are important to identify in metastatic CSPC, their immediate treatment implications are limited:

• No PARP inhibitors are currently FDA-approved specifically for the CSPC setting
• Standard treatment approaches for metastatic CSPC remain the same regardless of HRR mutation status
• Patients with HRR mutations respond similarly to standard therapies as those without mutations 1

Testing Recommendations

• Genetic testing for HRR mutations is recommended at diagnosis of metastatic prostate cancer
• Both germline and somatic testing should be considered
• Testing helps inform:
  1. Future treatment planning for when disease becomes castration-resistant
  2. Potential hereditary cancer risk for family members

Treatment Implications in mCRPC Setting

When CSPC progresses to mCRPC, HRR mutations become clinically actionable:

PARP Inhibitors

• Olaparib is FDA-approved for mCRPC with HRR mutations after progression on novel hormonal therapy 1

  • Most effective in BRCA1/2 mutations (HR for OS: 0.59; 95% CI, 0.37-0.95)
  • Less effective in ATM mutations (HR: 0.93; 95% CI, 0.53-1.75) 1

• Talazoparib plus enzalutamide is FDA-approved for HRR-mutated mCRPC (including BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) 1

• Niraparib plus abiraterone is FDA-approved for BRCA-mutated mCRPC 1

Heterogeneity of Response

Recent meta-analysis shows significant heterogeneity in PARP inhibitor response based on specific gene mutations 3:

• Strongest benefit: BRCA2 mutations
• Moderate benefit: BRCA1, PALB2 mutations
• Limited/no benefit: ATM, CHEK2 mutations

Platinum Sensitivity

• DNA repair defects may predict sensitivity to platinum agents in mCRPC
• Platinum agents have shown activity in mCRPC regardless of molecular selection
• Further studies of platinum agents specifically in HRR-mutated CRPC are needed 1

Special Considerations

CDK12 Mutations

• Associated with aggressive disease, high metastasis rates, and shorter overall survival
• Poor response to hormonal therapy, PARP inhibitors, and taxanes
• Potential response to PD-1 inhibitors (11-33% response rates) 1

Future Directions

1. Ongoing trials evaluating PARP inhibitors in earlier disease states, including metastatic CSPC
2. Combination strategies being explored:
   • PARP inhibitors + androgen receptor pathway inhibitors
   • PARP inhibitors + radiation or radioligand therapy
   • PARP inhibitors + immunotherapy 2, 4

Clinical Recommendation

For patients with metastatic CSPC and identified HRR mutations:

1. Follow standard treatment protocols for metastatic CSPC
2. Consider clinical trial enrollment if available 1
3. Plan for potential PARP inhibitor therapy if/when disease progresses to mCRPC
4. Consider genetic counseling for patients with germline mutations

Pitfalls to Avoid

• Don't assume all HRR mutations confer equal treatment benefit with PARP inhibitors
• Don't withhold standard therapies based on HRR mutation status
• Don't delay testing until castration resistance develops, as results may inform earlier treatment planning
• Recognize that response to PARP inhibitors varies significantly by specific gene mutation