BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) 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 177Lu 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 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 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 177Lu 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 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu 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. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Department of Internal Medicine 4 Nephrology and Hypertension Medical University Innsbruck Innsbruck Austria

Department of Nuclear Medicine Medical University Innsbruck Innsbruck Austria

Department of Nuclear Medicine University Hospital LMU Munich Munich Germany

Department of Nuclear Medicine University Hospital Tübingen Tübingen Germany

Department of Urology and Pediatric Urology University Medical Center Mainz Mainz Germany

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology University of Texas Southwestern Dallas TX USA; Department of Urology Weill Cornell Medicine New York NY USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia; Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia; Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Department of Urology Medical University of Vienna Vienna Austria; Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Medical University Innsbruck Innsbruck Austria

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology University Hospital Schleswig Holstein Campus Lübeck Lübeck Germany

Department of Urology University Hospital Tübingen Tübingen Germany

Department of Urology Uro Oncology Robot Assisted and Reconstructive Urologic Surgery University of Cologne and University Hospital Cologne Cologne Germany

Department Surgery Oncology and Gastroenterology Urologic Unit University of Padova Padova Italy

Division of Nuclear Medicine Medical University of Vienna Vienna Austria

Radiation Oncology Unit Veneto Institute of Oncology IRCCS Padua Italy

Unit of Urology Division of Oncology Gianfranco Soldera Prostate Cancer Laboratory IRCCS San Raffaele Scientific Institute Milan Italy

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