In-field progression following radiation therapy as a prognostic biomarker for lutetium-177-PSMA-617 response in metastatic castration-resistant prostate cancer.

86 Background: Prostate cancer often expresses prostate-specific membrane antigen (PSMA), which serves as a diagnostic and therapeutic target. Lutetium-177 ( 177 Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing sites. The prognostic implications of in-field progression (IFP) following prior radiation treatment (RT) on 177 Lu-PSMA-617 response in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: We retrospectively reviewed our experience with 177 Lu-PSMA-617 in mCRPC delivered at multiple community-based practices in the Mountain West. Exclusion criteria included death unrelated to prostate cancer before cycle 3 of 177 Lu-PSMA-617 and completing < 4 cycles by June 1 st , 2024. Baseline characteristics and treatment history were collected. Baseline PSMA PET/CTs were evaluated for maximum SUV, visceral metastases, and lesional heterogeneity (LH) and correlated with radiation records to determine IFP. Progression-free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier and Logrank analysis, and Cox proportional hazard model was used for univariate (UV) and multivariate (MV) analysis of suspected risk factors. Results: In total, 72 patients were evaluated with a median follow-up of 10.9 months. Median PFS was 6.5 months (95%CI [4.4 – 9.3]), and median OS was 15.0 months (95%CI [10.9 – undefined]). Fifty-nine patients received either palliative or definitive RT courses for prostate cancer prior to receiving 177 Lu-PSMA-617. Of the 59 patients, 25 patients demonstrated IFP, 34 did not. In-field progression (UV: HR 2.5, p=.003; MV: HR 2.7, p=.003) and LH (UV: HR 1.9, p=.025; MV: 2.1, p=.036) were found to be risk factors for progression during 177 Lu-PSMA-617 therapy. Median PFS among patients with IFP was 3.9 mo (95%CI [2.6 – 6.3]) versus 10.3 mo (95%CI [4.4 – 13.0]) among those without (p=.002). Median PFS among patients with LH was 4.6 mo (95%CI [2.9 – 6.5]) versus 11.6 mo (95%CI [6.9 – 13.0]) for those without (p=.023). IFP (UV: HR 2.5, p=.016; MV: 2.7, p=.021; median OS = 10.2 mo, 95%CI [6.2 – 12.8]) and LH (UV: HR 2.45, p=.027; MV: HR 4.17, p=.018; median OS = 11.7 mo, 95%CI [9.3 – 15.0]) were similarly prognostic for OS. At the current follow-up, median OS has not been reached for patients without IFP or LH, but Logrank testing shows statistically significant improvements in OS for these groups (p=.013 and p=.022, respectively) over those with them. Conclusions: In our real-world experience, PFS and OS for 177 Lu-PSMA-617 in mCRPC were similar to the VISION study results. IFP following RT and LH on baseline PSMA PET/CT were negative prognostic biomarkers. Validation in a larger, prospective cohort is warranted.