267P - Exploring homologous recombination deficiency threshold for predicting response to PARP inhibitor in prostate cancer

Background

Homologous recombination deficiency (HRD) score serves as a promising biomarker to identify patients who are eligible for treatment with PARP inhibitor (PARPi). Previous studies have suggested a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42 is a valid biomarker to predict response to PARPi in patients with ovarian cancer. However, the GIS threshold for prostate cancer (PCa) is still lacking. Here, we conducted an exploratory analysis to investigate an appropriate GIS score and to evaluate its ability to predict response to PARPi in prostate cancer patients.

Methods

A total of 225 patients with PCa were included in this study. Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair (HRR) genes and promoter methylation analysis. GIS score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. The HRD score threshold was set at the 5th percentile of the GIS scores in our cohort of known BRCA1/2-deficient tumors which is the method used to define the HRD threshold in breast and ovarian cancer.

Results

In our cohort, 22 patients (9.78%) had BRCA1/2 mutations or BRCA1/2 promoter methylation, with additional 32 patients (14.22%) carrying mutations in HRR genes. The median HRD score was 2 (ranged from 0 to 78) in total cohort which is much lower than that of in breast and ovarian cancer. The 5th percentile of HRD scores was 9 in the BRCA1/2-deficient cohort and consequently high HRD was defined as HRD scores >9. In the 12 patients who received PARPi in our cohort, 8 patients with a high HRD score achieved a disease control rate of 83.3%. In addition, 4 patients with a low HRD score but with mutations in HRR genes other than BRCA1/2 achieved a disease control rate of 25.0%.

Conclusions

HRD positive, defined as GIS score >9, may be an appropriate threshold to predict the likelihood of response to PARPi in prostate cancer. Prospective, and large sample clinical trials will be needed to confirm our findings.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J. Wang.

Funding

China Anti-Cancer Association-Hengrui PARP Inhibitor Cancer Research Fund (Phase I).

Disclosure

All authors have declared no conflicts of interest.