Impact of genomic alterations on outcomes in patients with metastatic castration resistant prostate cancer (mCRPC) treated with Lu-177 radioligand therapy (RLT).

e17099 Background: The genomic landscape of mCRPC has been shown to effect response to certain therapies (e.g. PARP inhibitors); however, the impact of mutation status on patients undergoing Lu-177 PSMA RLT is not well described. Methods: We identified and retrospectively reviewed the electronic medical record of patients with mCRPC who received at least one cycle of Lu-177 PSMA RLT at one of two academic institutions (Stanford University and Oregon Health & Science University) between 3/2019 – 9/2023. Clinical data, including germline and somatic mutation status, were collected. Progression was defined radiographically or per documentation by the treating clinician. Associations between patient characteristics and prostate specific antigen (PSA) response were assessed using logistic regression; associations with survival utilized the Cox proportional hazards model. Time from first Lu-117 PSMA RLT cycle to progression (PFS), next line of therapy (TTNT), and/or death (OS) was estimated using the Kaplan-Meier method. Results: 180 patients were included in our analysis. 159 (88%) had completed genetic testing. 16 (9%) carried a BRCA 1 or 2 mutation, 27 (15%) had a non- BRCA homologous repair deficiency (HRD) mutation (e.g. ARID1A , ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D/54L ), and 76 (42%) had a mutation in p53, RB1, or PTEN. 2 (1%) were microsatellite unstable. Median number of prior lines of therapy was 5; 16 (9%) had received a PARP inhibitor (6/16: BRCA mutated; 10/16: non- BRCA HRD mutated) and 139 (77%) had received a taxane. Mean number of Lu-177 PSMA RLT cycles was 4. Reduction in PSA ≥50% (PSA50) was achieved in 92/180 (51%) and a reduction ≥90% (PSA90) was achieved in 45/180 (25%). Median PFS was 7 months, median TTNT was 9 months, and median OS was 12 months for the entire cohort. See table 1 for associations between PSA50/PSA90/OS and mutation status. Patients with non-BRCA HRD mutation had significantly higher PSA90 but no significant difference in PSA50 or OS. No other significant association was appreciated. Conclusions: In our multicenter cohort of mCRPC patients receiving Lu-177 PSMA RLT, patients with non- BRCA HRD mutations achieved significantly higher PSA90 without significant difference in OS. Limitations include retrospective study design and modest sample size. Mutation (vs. without specific mutation) PSA50, % PSA90, % OS, months BRCA1 60 vs 50, p = 0.65 40 vs 23, p = 0.37 13 vs 12, p = 0.82 BRCA2 36 vs 51, p = 0.35 9 vs 24, p = 0.28 12 vs 12, p = 0.85 CDK12 50 vs 50, p = 1.0 25 vs 23, p = 0.93 10 vs 13, p = 0.09 BRCA1/2 or CDK12 45 vs 51, p = 0.56 20 vs 26, p = 0.59 12 vs 12, p = 0.48 Non- BRCA HRD 63 vs 47, p = 0.14 41 vs 19, p = 0.02 13 vs 12, p = 0.90 PTEN 58 vs 48, p = 0.36 38 vs 20, p = 0.07 12 vs 12, p = 0.57 RB1 50 vs 50, p = 0.98 13 vs 23, p = 0.48 15 vs 12, p = 0.44 TP53 45 vs 51, p = 0.51 16 vs 26, p = 0.20 11 vs 13, p = 1.18 Any 2: PTEN, RB1, TP53 42 vs 50, p = 0.56 25 vs 23, p = 0.86 12 vs 13, p = 0.51