Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• PARP inhibitors show efficacy in advanced prostate cancer (APC) with DNA repair defects.
• Identifying predictive biomarkers for PARP inhibitor response remains a clinical challenge.

Purpose of the Study:

• To analyze clinical trial samples to identify biomarkers predicting response to PARP inhibitors in advanced prostate cancer.
• To evaluate the association between specific gene alterations (BRCA1/2, PALB2, ATM, CDK12) and homologous recombination repair (HRR) function with clinical benefit.

Main Methods:

• Analysis of whole-exome and low-pass whole-genome sequencing data from the TOPARP-B phase II clinical trial.
• Immunohistochemistry (IHC) and immunofluorescence (IF) assays to assess ATM protein and RAD51 foci (as a measure of HRR function).

Main Results:

• Germline and somatic BRCA1/2 mutations conferred similar benefit; homozygous BRCA2 deletion showed greater benefit.
• Biallelic PALB2 alterations, but not monoallelic, were associated with clinical benefit.
• Loss of ATM protein by IHC and loss of RAD51 foci were linked to better outcomes and specific genetic alterations (biallelic BRCA/PALB2 for foci loss).

Conclusions:

• Not all advanced prostate cancers with DNA repair defects benefit equally from PARP inhibitors.
• Homozygous BRCA2 deletion, biallelic PALB2 loss, and ATM protein loss are key predictors of PARP inhibitor benefit.
• RAD51 foci loss serves as a functional biomarker for homologous recombination repair deficiency, particularly in BRCA/PALB2 altered tumors.