A prospective study of comprehensive genomic testing to identify actionable variants in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shevrin Daniel , Yang Mathew , Sabatini Linda , Pfanzelter Nicklas , Akroush Michael , Alnajar Hussein , Helseth Larry 
Published: January 2024

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Background: Genomic testing in pts with mCRPC has become an important tool to identify actionable variants, in particular with an on-label treatment recommendation. Testing previously required tumor tissue, but cfDNA is now approved as a companion diagnostic for specific HRR variants. In this prospective study at a community-based hospital, we conducted comprehensive genomic testing to identify pts with actionable variants. We report results on variants specifically with an on-label treatment recommendation. Methods: Pts with mCRPC had genomic testing with cfDNA using the PredicineCare NGS assay and germline and tissue (archival and metastasis when available) using the NorthShore Expanded Cancer NGS Panel. Sequence data were entered into Flype, our in-house software used for secondary analysis, annotation of NGS results, and report sign-out. Clinical outcomes data were obtained using a structured note and selected pts were discussed at a molecular tumor board. Results: Of the 108 enrolled pts, all had germline and cfDNA testing. Results from tumor tissue were obtained in 48 pts (archival in 19, metastasis in 22, and both in 7). Overall, 42 pts (38%) had 1 or more variants with a recommendation for an on-label treatment. Of these, 40 pts had 1 or more HRR variants (BRCA1/2 in 19, ATM in 7, CHEK2 in12, CDK12 in 3, other in 2) and 2 pts had MSI-H. Of the 19 BRCA1/2 variants reported, 14 were deletions and detected by cfDNA. Treatment was recommended in 7 of these pts whose testing was done after there was a change in the level of evidence supporting this recommendation. The 7 pts with BRCA1/2 deletions reported prior to this change are included in the total. Repeat cfDNA testing in 16 pts with tumor progression detected a new HRR variant in 7 pts. They are included in the total. Of the 42 pts with a treatment recommendation, 23 pts (56%) have received an on-label treatment, 19 with a PARP inhibitor and 4 with pembrolizumab. Of the 48 pts with both tissue and cfDNA results, 19 had variants with a treatment recommendation, with cfDNA detecting 68%, tissue 16%, and both in 16%. Conclusions: In this prospective study, 38% of pts with mCRPC were identified to have variants with an on-label treatment recommendation, highlighting the value of comprehensive testing to identify a relatively high number of these pts. In pts with both cfDNA and tissue testing, cfDNA alone detected 68% of these pts, emphasizing the value of cfDNA as a complement or alternative to tissue testing. Repeat cfDNA testing in a cohort of pts detected a new on-label variant in almost half of the pts tested, emphasizing the potential value of serial testing with tumor progression. As of this report, 56% of pts have received treatment with an on-label drug and clinical outcomes are being evaluated. Pts with other potentially actionable variants are being evaluated for off-label treatment or clinical trials.