Association of genomic alterations with clinical outcomes following lutetium-177-PSMA vipivotide tetraxetan in men with metastatic castrate-resistant prostate cancer.

5057 Background: Lutetium-177-PSMA vipivotide tetraxetan (Lu177) is approved for men with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC) previously treated with androgen receptor signaling inhibitors and taxane chemotherapy. The tumor genomic alterations conferring sensitivity or resistance to Lu177 are unknown. We investigated the association of genomic variants with clinical outcomes in men with mCRPC treated with Lu177. Methods: Somatic & germline DNA sequencing data were examined from men treated with ≥1 cycle Lu177 at The James Cancer Hospital of The Ohio State University from 3/2022 – 10/2023. Pathogenic variants from tissue or blood testing were identified. Sets of genes with similar biological function were annotated, including homologous recombination repair (HRR) genes ( BRCA1, BRCA2, ATM, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), established tumor suppressor genes ( TP53, RB1, PTEN) and cell cycle genes ( CCND1, CCND3, CDK4, CDK6, CDK12, CDKN1B, CDKN2B) associated with prostate cancer. The impact of genomic variants on PSA50 response (Chi-Square & Fisher’s exact test), median overall survival (OS) and median progression-free survival (PFS) (Kaplan-Meier method) and OS or PFS (Cox proportional hazards model) was assessed. Results: Of 153 patients treated with Lu177, 120 underwent genomic sequencing: 109 had somatic testing (76 tissue-based, 33 blood-based), 50 had germline and 39 had both somatic & germline testing. Patients with amplification of cell cycle genes (n=8) had poorer OS of 5.1 months (mos.) vs 13.4 mos. for those without amplification (p=0.001, HR 4.26, 95% CI 1.79-10.11), and shorter PFS of 4.3 vs 7.4 mos. (p=0.027, HR 2.40, 95% CI 1.10-5.22). Patients with loss or mutation of HRR genes (n=32) had OS of 13.7 vs 12.2 mos. for those with no HRR alterations, but this was not significant (p=0.101, HR 0.57, 95% CI 0.29-1.12). No other genomic alterations were significantly associated with OS or PFS and none were associated with PSA50 response. The table lists the most frequently altered genes in PSA50 responders vs non-responders (differences not significant by Fisher’s exact test). Conclusions: Genomic alterations warrant investigation in larger cohorts as prognostic and predictive biomarkers for Lu177 therapeutic response. Our data suggest that amplification of genes impacting cell cycle regulatory pathways may be of particular interest. Our findings support continued efforts to determine the impact of cyclin dependent kinase (CDK) 4/6 inhibitors for high-risk and metastatic prostate cancer, either alone or in combination with agents such as Lu177.Table: see text