Background: ¹⁷⁷Lu-PSMA-617 is approved for the treatment (tx) of mCRPC. Though tx is associated with improved survival, not all pts experience a benefit. Acquired resistance is common and some pts have intrinsic resistance. There is a lack of data on genomic markers that could aid in selecting pts for tx. In this study, we aim to characterize molecular predictors of benefit to ¹⁷⁷Lu-PSMA-617. Methods: We used the retrospective Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n=2100). The primary endpoint was to investigate the association of genomic alterations with a ≥50% PSA decline (PSA50) from baseline following ¹⁷⁷Lu-PSMA-617. Associations were assessed using Wald-chi square test and Cox regression in multivariable analysis. Secondary endpoints included clinical progression-free survival (PFS) and overall survival (OS). Results: We identified 115 pts with PSMA PET+ mCRPC treated with ¹⁷⁷Lu-PSMA-617 who had commercial genetic sequencing prior to tx (median age 72 yrs, 25% non-white). Median number of prior lines for mCRPC was 3 with 71 pts (62%) receiving >1 androgen receptor signaling inhibitor (ARSI) and 55 pts (48%) receiving >1 taxane; 11 pts (9%) received ARSI with ¹⁷⁷Lu-PSMA-617. Overall, the PSA50 was 49% with median OS and PFS of 14.0 and 7.6 months (mos), respectively. In pts with a PSA50, median OS and PFS were 22.6 and 11.6 mos, respectively, vs 11.2 and 5.6 mos for those without a PSA50. Genetic alterations associated with PSA50 are in the table. PSA50 was 48% in pts with (n=32) vs 49% in pts without DDR alterations (n=83). PSA50 was 44% in pts with tumor suppressor gene alterations (TSGa) (PTEN, p53, RB1) (n=68) vs 56% in pts without (n=47). Median PFS was 7.6 vs 7.3 mos for pts with and without any TSGa (p=0.90), and median OS was 12.2 mos vs 22.6 mos for pts with and without TSGa (p=0.004). Of the 43 pts with AR alterations, 8/15 (53%) with LBD mutations, 10/27 (37%) with AR amplification, and 0/1 with AR-V7 had a PSA50. FGFR, CDK12 and MYC alterations were enriched in individuals without a PSA50 (75-83%). Conclusions: We demonstrate that CDK12, MYC and FGFR alterations were associated with a lower PSA50 with ¹⁷⁷Lu-PSMA-617. Larger cohorts should be investigated for confirmation, as biomarkers to inform relative benefit of tx could be useful in prioritizing options for mCRPC.