219 Background: The HRDsig biomarker has emerged as a putative predictor of PARP inhibitor (PARPi) efficacy in multiple tumor types including CAPC. Previous studies of HRDsig+ CAPC focused on BRCA1/2 genomic alterations (GA); while non-BRCA ( BRCA1/2 wt) GA have not been widely considered as drivers of HRDsig+ CAPC PARPi response. Methods: Using the FoundationOne CDx assay, 23,336 BRCA1/2 wt CAPC cases underwent hybrid capture based CGP to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI), tumor mutation burden (TMB), HRD signature (professional services assay), genomic ancestry and genomic signature were determined from the sequencing data. PD-L1 expression was determined by IHC using Dako TPS score (≥1%: positive). Comparisons were evaluated by χ2 2-tailed using the Yates correction. Results: In this analysis of BRCA1/2 wt CAPC only, 1,107 (4.7%) were HRDsig+. Men with BRCA1/2 wt HRDsig+ CAPC were slightly older (median age 71 vs 69; p<.0001) and featured a slightly higher median number of GA per tumor (4 vs 3; p<.0001). Genomic ancestry distribution revealed just slightly higher African ancestry in the BRCA1/2 wt HRDsig- CAPC (15.2% vs 12.5%; p<.0001) and just slightly higher European ancestry in the BRCA1/2 wtHRDsig+ cases (77.9% vs 74.7%; p=.020). Putative biomarkers of anti-PD1/L1 response including TMB ≥ 10 mut/Mb (range 3.0% to 2.2%; NS) and PD-L1 expression ≥1% (range 10.8% to 11.2%; NS) were similar, although the highly infrequent MSI-high status was more frequent in the BRCA1/2 wt HRDsig- CAPC group (2.2% vs 0.6%; p<.0001). Individual GA more frequent in the BRCA1/2 wt HRDsig+ CAPC involved AR (23.4% vs 10.1%; p<.0001), ATM (8.3% vs 5.7%; p=.0004), FANCA (1.7% vs 0.9%; p=.01), MYC (17.1% vs 8.8%; p<.0001), PTEN (36.1% vs 32.5%; p=.013), RAD21 (12.6% vs 6.1%; p<.0001), RB1 (8.7% vs 4.6%; p<.0001) and TP53 (48.8% vs 38.5%; p<.0001). GA more frequent in the BRCA1/2 wt HRDsig- CAPC included CDK12 (5.3% vs 2.2%; p<.0001), SPOP (11.6% vs 7.2%; p<.0001) and TMPRSS2 (32.4% vs 29.9%; NS). Although relatively uncommon, chromosome 9p loss including CDKN2A / B and MTAP were more frequent in the BRCA1/2 wt HRDsig+ CAPC (MTAP 3.1% vs 1.6%; p=.003). Conclusions: The genomic landscape of BRCA1/2 wt CAPC with HRDsig+ status seems relatively distinct from HRDsig- BRCA1/2 wt cases, involving HRD pathway-associated and other genes that may impact prognosis and help guide clinical trial designs. Limitations include retrospective nature and lack of clinical outcomes data annotation. CAPC HRDsig- (22,229 cases) CAPC HRDsig+ (1,107 cases) P Value AR 10.1% 23.4% <.0001 ATM 5.7% 8.3% 0.0004 CDK12 5.3% 2.2% <.0001 FANCA 0.9% 1.7% 0.01 RAD21 6.1% 12.6% <.0001 RB1 4.6% 8.7% <.0001 SPOP 11.6% 7.2% <.0001 TMPRSS2 32.4% 29.9% NS
Gebrael et al. (Sun,) studied this question.