Clinical outcomes from a prospective study of comprehensive genomic testing in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniel Shevrin, Mathew Yang, Linda Sabatini, Nicklas Pfanzelter, Michael Akroush, Hussein Alnajar, Henry Wittich, Larry Helseth
Journal: Journal of Clinical Oncology (2025)

216 Background: In this prospective study at a community-based hospital, we conducted comprehensive genomic testing to identify pts with actionable variants. We previously showed that this resulted in identification of 38% of pts with a recommendation for treatment, predominantly with a PARP inhibitor (PARPI). We now report on the clinical outcomes of pts who received treatment based on this genomic testing. Methods: Pts with mCRPC had genomic testing with cfDNA using the PredicineCare NGS assay and germline and tissue (archival and metastasis) using the Northshore Expanded Cancer NGS Panel. Repeat cfDNA testing was done in pts when they showed cancer progression. Response to genomic-directed treatment (GDT) was evaluated by clinical or radiographic PFS (crPFS) and &gt; 50% decrease in PSA from baseline (PSA50). Results: Of 138 enrolled pts, all had germline and cfDNA testing. Tumor tissue was obtained in 60 pts (archival 41%, metastasis 46%, both 13%). Repeat cfDNA testing was done in 25% of pts. Overall, 59 pts (43%) had a variant with a treatment recommendation. Testing with cfDNA alone identified 68% of which 28% were repeat. An HRR variant was detected in 57 pts (BRCA2 40%, ATM 14%, CHEK2 21%, CDK12 7%, other 13%). Of the 59 pts, 51% have received a GDT with a PARPI or pembrolizumab. Repeat cfDNA testing identified 27% of these pts. Reasons for no treatment included pts who had not yet received GDT as they were receiving effective treatment or pts with a poor performance status. The median crPFS was 4 months; 95% CI (1-11). There was no difference in PFS between pts with BRCA2 vs non-BRCA2 or repeat vs no repeat testing. A PSA50 was observed in 31% of pts (63% had a BRCA2). There was no difference between pts with BRCA2 vs non-BRCA2 or repeat vs no repeat testing. The median number of treatments for mCRPC prior to GDT was 2; 95% CI (1-6). There was a trend for longer PFS in pts receiving ≤ 2 vs &gt; 2 prior treatments (5.3 vs 3.6 m; p=0.09). Of the pts receiving GDT, 57% had Group 4 or 5 Gleason, 37% had visceral metastasis, and 40% had &gt; 10% weight loss. The median cfDNA fraction was 40.4%. Conclusions: In this prospective study done in a community setting, comprehensive genomic testing resulted in a relatively large number (43%) of pts with a treatment recommendation. Most of these pts (68%) were identified by cfDNA alone that also included repeat testing upon progression. Thus far, half of these pts have received a GDT with treatment available in the future for the others. The short PFS and low PSA50 are likely related to the pts being heavily pretreated and having a high tumor burden. This is expected in pts with late-stage mCRPC and corroborates the value of earlier use of GDT, although treatment in these pts still resulted in clinical benefit. Repeat cfDNA testing helped identify additional pts with a treatment recommendation, but further studies are required to define the validity of this testing.