PARP Inhibitors in Metastatic Prostate Cancer: Bridging Biomarker Complexity and Clinical Decision-Making Through a...

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Metastatic prostate cancer treatment is evolving with biomarker-driven strategies targeting homologous recombination repair (HRR) alterations.
• Poly(ADP-ribose) polymerase inhibitors (PARPi) show efficacy, particularly in tumors with Breast Cancer genes 1/2 (BRCA) alterations, via synthetic lethality.
• Increasing PARPi use across treatment settings complicates patient selection, sequencing, and biomarker interpretation.

Purpose of the Study:

• To provide a clinically applicable, decision-oriented framework for PARP inhibitor use in metastatic prostate cancer.
• To move beyond descriptive trial synthesis towards practical clinical guidance.

Main Methods:

• Conducted a narrative review of pivotal phase II and III trials (2020-2026) on PARPi monotherapy and combination strategies.
• Critically analyzed evidence focusing on biomarker relevance, treatment positioning, and real-world applicability.

Main Results:

• PARPi improve radiographic progression-free survival, with the greatest benefit in BRCA-altered prostate cancer.
• Non-BRCA HRR alterations show heterogeneous predictive value, challenging a binary biomarker approach.
• Combination strategies in first-line metastatic castration-resistant prostate cancer (mCRPC) expand options but raise concerns about toxicity and benefit in unselected populations.

Conclusions:

• PARP inhibitors are central to precision oncology for metastatic prostate cancer, requiring a refined, biomarker-informed approach.
• A pragmatic 2026 clinical decision framework integrating molecular, treatment, and clinical factors is proposed.
• This framework aims to align clinical trial evidence, guidelines, and real-world practice for optimal PARPi utilization.