Serum biomarkers in metastatic castration-resistant prostate cancer (mCRPC) patients receiving [ ¹⁷⁷ Lu]Lu-PSMA-617 therapy: Post hoc analysis of a phase II clinical trial.

190 Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) has been recently approved for metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have assessed the efficacy of 177 Lu-PSMA-617, but only half of the eligible patients seem to obtain a clear benefit from it. Currently, there is a lack of validated biomarkers that could help find the best candidates for this radioligand therapy. Methods: In the IRST185.03, a single-arm monocentric phase II clinical trial, 142 mCRPC patients received 177 Lu-PSMA-617 at a dose of 3.7-5.5 Gbq every 8-12 weeks for a maximum of 4 cycles. Baseline blood samples were collected within 7 days from the first dose of 177 Lu-PSMA-617. Hemoglobin (Hb), alkaline phosphatase (ALP), prostate-specific antigen (PSA), carcinoembryonic Antigen (CEA), chromogranin A (CgA), and neuron-specific Enolase (NSE), as well as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were analyzed at both uni- and multivariate levels to evaluate their correlation to progression-free survival (PFS). Results: At the time of data cut-off, after a median follow-up time of 44.0 months, the median PFS in the global cohort was 7.0 months. At univariate analysis, among serum biomarkers, lower PLR (cut-off: 210, HR: 0.66, 95% CI: 0.44-0.99, p=0.04), lower ALP (cut-off: upper limit of normal, HR: 0.51, 95% CI: 0.34-0.75, p<0.01), lower PSA (cut-off: median value, HR: 0.51, 95% CI: 0.35-0.74, p<0.01), and lower CEA (cut-off: upper limit of normal, HR: 0.55, 95% CI: 0.32-0.95, p=0.03) were associated with longer PFS. Among clinical characteristics, the previous use of docetaxel (HR: 1.48, 95% CI: 1.04-2.10, p=0.03) was associated with shorter PFS. At multivariate analysis, only PSA and CEA remained prognostic for PFS (p=0.01 and 0.02. respectively). Conclusions: High PSA and CEA levels appeared the only serum predictors of poor clinical outcome to 177 Lu-PSMA-617 therapy in mCRPC. The role of CEA as potential biomarker associated with 177 Lu-PSMA-617 needs to be confirmed since it could be linked to aggressive prostate cancer variant. Clinical trial information: 2016-002732-32 .