Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study

Background: The European Association of Urology guidelines include the lutetium-177 (Lu-177) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. Objective: To assess the performance of Lu-177 PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. Design, setting, and participants: We conducted a retrospective observational study including 233 patients with mCRPC treated with Lu-177 PSMA in eight high-volume European centers. Outcome measurements and statistical analysis: Baseline characteristics and clinical parameters during and after Lu-177 PSMA treatment were documented. Correlations to treatment response were analyzed using chi(2) and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. Results and limitations: A prostate-specific antigen (PSA) decrease of >= 30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease >= 30% after the first two cycles of Lu-177 PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase <= 31 U/L at the start of Lu-177 PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). Conclusions: Lu-177 PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease >= 30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice.