Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.

e17063 Background: We aim to elucidate associations between mutations, treatment response, and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients undergoing Lu-177 PSMA radioligand therapy (PSMA-RLT). Methods: We reviewed mCRPC patients who received at least 1 cycle of PSMA-RLT between May 2022 and October 2023, assessing mutations that included ATM, ATR, BRCA1/2, BRIP1, CHEK2, EPCAM, FANCA, GEN1, HOXB13, MLH1, MSH2/6, NBN, PALB2, PMS2, RAD51C, RAD51D, and TP53. Clinical variables were collected. Biochemical response (BR) was defined as PSA reduction ≥ 50% over the complete course of PSMA-RLT. PSMA PET segmentation was performed with MIM PUR PSMA (version 7.2.9). OS was measured from start of PSMA-RLT, estimated by the Kaplan-Meier method, and modeled with Cox regression; BR was modeled with logistic regression. Results:71 mCRPC patients with median age of 72 (range: 48-90) were included. 47 (66%) patients completed ≥ 4 PSMA-RLT cycles with 30% receiving all 6 cycles. 35 (49%) had a GS ≥ 8 (11 unknown) and 33 (46%) had metastases at diagnosis. 25 patients had somatic testing, 29 had germline testing, 16 had both, and 1 was unknown. All tumors were microsatellite stable. 6 had a BRCA 1/2 mutation, of which 3 were in the germline; 9 carried a non- BRCA homologous recombination deficiency (HRD) mutation. 17 had a mutation in p53, RB1, or PTEN. There was no correlation between mutation status and any pretreatment PET parameters, BR, or OS. BR was achieved in 48%. At median follow-up of one year, 41% of patients died; median OS was 12 months (95%CI: 10 – NA). No significant correlation was found when comparing prior therapy, mutation status, and any pretreatment PET parameter with BR or OS. Patients receiving all 6 cycles were 7 times more likely to achieve BR (p = 0.002). Conclusions: There was no significant association between PSMA-RLT outcomes and either mutation status or pretreatment PET parameters. This study is limited by the low number of patients with genomic alterations. Table: see text