Homologous recombination deficiency signature (HRDsig+) and the genomic landscape of clinically advanced prostate carcinoma (CAPC).
Authors: Chiara Mercinelli, Philippe E. Spiess, Roger Li, Ashish M. Kamat, Petros Grivas, Shilpa Gupta, Neeraj Agarwal, Liang Cheng, Dean Pavlick, Ethan Sokol, Ryon P Graf, Jeffrey S. Ross, Alexa Betzig Schrock, Julia Quintanilha, Gerald Li, Douglas I Lin, Joseph M Jacob, Gennady Bratslavsky, Alina Basnet, Andrea Necchi
Journal: Journal of Clinical Oncology (2025)

196 Background: CAPC is very challenging with significant need for improvement in systemic therapy, including for patients (pts) with incurable disease. Recently a novel HRDsig biomarker has been linked to clinical outcomes after PARP inhibitor-based treatments. We aimed to explore HRD sig status and related biomarkers, including other GA, to generate hypothesis and inform clinical trial designs for pts with CAPC. Methods: 22,061 cases of CAPC underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features.PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: Overall, 2,244 (10.2%) of CAPC cases were HRDsig+. There were slightly more MSI-high cases in the HRDsig- vs HRDsig+ CAPC (3.1% vs 0.5%; P&lt;.0001). Both TMB and PD-L1 levels were low and varied in both groups. HRD associated GA included BRCA2 and RAD21 were more frequent in the CAPC HRDsig+ cases. BRCA1 GA were extremely rare in both groups. In the HRDsig- group, 90%/49% of BRCA1 / BRCA2 mutated CAPC were mono-allelic, likely non-driver GA, respectively Higher frequencies of GA in CDK12 and SPOP (11.1% vs 5.9%; P&lt;.0001) were found in HRDsig- cases and a higher frequency of AR GA in HRDsig+ cases. MTOR pathway related GA in PTEN were similar, although homozygous deletions of PTEN were more frequent in the HRDsig- cases (22.2% vs 19.2%; P=.0009; Table). Conclusions: With a 10.2% frequency, HRDsig+ status is a relatively common biomarker in CAPC. HRDsig+ status was associated with a higher frequency of BRCA2 GA, including homozygous deletions in &gt;20% of these pts, which has been associated with prolonged benefit from PARPi in selected pts. Given that likely non-driver mono-allelic BRCA1/2 GA are frequently identified in HRDsig- CAPC, mono-allelic GA may not be associated with HRDsig status and might not yield similar clinical benefit from PARPi. Limitations include the retrospective nature, potential selection bias and lack of clinical outcomes annotation. Main differences in GA classes between HRDSig- and HRDSig+. HRDSig- HRDSig+ P value Age (yrs) 68 70 &lt;.0001 AFR ancestry 15.4% 13.1% 0.0110 AR 10.8% 17.3% &lt;.0001 BRCA2 mutation 3.3% 52.3% &lt;.0001 BRCA2 homozygous deletion 0.6% 21.4% &lt;.0001 CDK12 5.5% 1.2% &lt;.0001 RAD21 7.2% 16.3% &lt;.0001 MMR sig 4.0% 2.0% &lt;.0001 TMB≥10 mut/Mb 4.4% 3.7% NS