PARP Inhibitor Plus Androgen-receptor Signaling Inhibitor Versus the Same Inhibitor Alone in...

Area of Science:

• Oncology
• Medical Genetics
• Clinical Trials

Background:

• Metastatic prostate cancer with homologous-recombination-repair (HRR) alterations benefits from PARP inhibitors (PARPi) and androgen-receptor signaling inhibitors (ARSI).
• Uncertainty exists regarding treatment effects across different disease states and specific genomic subgroups within HRR-altered prostate cancer.

Purpose of the Study:

• To evaluate the efficacy of combining PARP inhibitors with ARSI compared to ARSI alone in HRR-altered metastatic prostate cancer.
• To explore treatment effects across distinct genomic subgroups (BRCA vs. non-BRCA) and disease states (metastatic hormone-sensitive vs. metastatic castration-resistant).

Main Methods:

• A systematic literature search was conducted across major databases for randomized controlled trials up to June 2026.
• Meta-analysis of trial-level data using random-effects models (REML) with Hartung-Knapp confidence intervals.
• Exploratory analyses included subgroup comparisons by BRCA/non-BRCA status and disease state, and a paired ratio-of-hazard ratios analysis.

Main Results:

• The combination of PARPi plus ARSI significantly improved radiographic progression-free survival (rPFS) overall (HR 0.56).
• A larger benefit was observed in BRCA-altered disease (HR 0.36) compared to the heterogeneous non-BRCA group (HR 0.75).
• Pooled overall survival showed a trend towards benefit (HR 0.75), but with interim data from two trials. Grade ≥ 3 adverse events were increased.

Conclusions:

• PARPi plus ARSI combination therapy enhances rPFS in HRR-altered metastatic prostate cancer.
• The observed greater efficacy in BRCA-altered disease warrants further investigation, acknowledging the heterogeneity of non-BRCA alterations.
• While a survival benefit signal exists, it must be weighed against increased toxicity and requires confirmation with mature data.