BRCA Mutations in mHSPC: Impact on Therapy Selection

Clinical Brief: Genetic Considerations in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Main Discussion Topics

• Implications of BRCA Mutations: More aggressive molecular phenotype requiring consideration of treatment intensification
• Genetic Counseling: Recommended for all BRCA-positive patients due to implications for family members and risk of second malignancies
• Treatment Strategy Modification: Support for triplet therapy with androgen deprivation therapy, chemotherapy, and androgen receptor targeting agent
• Future Therapy Planning: Early integration of PARP inhibitors when castration resistance develops

Key Points for Physicians

• Multiple clinical trials support PARP inhibitor use in castration-resistant disease with HRR mutations:
  • TALAPRO trial (talazoparib with enzalutamide)
  • PROpel trial (olaparib with abiraterone)
  • MAGNITUDE trial (niraparib with abiraterone)
  • PROfound trial (olaparib as single agent)
  • TRITON trial (rucaparib as single agent)
• Trial data should influence initial androgen receptor–targeted agent selection
• PARP inhibitors not currently indicated for hormone-sensitive disease

Notable Insights

The presence of HRR mutations warrants consideration of more aggressive upfront treatment approaches, even in borderline high-volume disease, and planning for earlier integration of PARP inhibitors upon disease progression.

Clinical Significance

Genetic testing results significantly influence both immediate treatment decisions and long-term therapeutic planning in metastatic prostate cancer management, underscoring the importance of precision medicine approaches.