Lutetium-177 PSMA radioligand therapy in taxan-naive first- and second-line metastatic castration resistant prostate cancer after first-line ARPI therapy.
Authors: Philipp Mandel, Benedikt Hoeh, Carolin Siech, Florestan Koll, Clara Humke, Daniel Groener, Thomas Steuber, Markus Graefen, Tobias Maurer, Severine Banek, Felix Chun, Mike Wenzel
Journal: Journal of Clinical Oncology (2025)

79 Background: Lutetium-177 Prostate-specific membrane antigen (Lu-PSMA) radioligand therapy is EMA-approved for metastatic castration resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. However, its effect in taxane-naïve patients is under current investigation. Methods: We relied on the FRAMCAP database to elaborate Lu-PSMA therapy outcomes of progression-free (PFS) and overall (OS) in taxane-naïve mCRPC patients after previous ARPI treatment. Comparison was made against current standard of care with ARPI or docetaxel. Results: Of 269 patients, 11% received Lu-PSMA in first/second-line mCRPC vs. 57% ARPI vs. 33% docetaxel. Mostly no significant baseline differences between Lu-PSMA and ARPI patients were observed, while Lu-PSMA patients were significantly older, received less systematic treatments and ECOG1-2 proportions were higher, relative to docetaxel patients. In PFS (13.3 vs. 8.2 months, hazard ratio [HR]: 0.70, p=0.16) and OS analyses (68.9 vs. 39.1 months, HR: 0.64, p=0.2), Lu-PSMA was numerically more favorable than ARPI. In additional multivariable Cox regression models, Lu-PSMA was significant better regarding PFS and OS, relative to ARPI (both p&lt;0.05). Compared to docetaxel, also significant better PFS (13.3 vs. 8.1 months, HR: 0.46) and OS (68.9 vs. 27.3 months, HR: 0.34, both p&lt;0.01) was observed for Lu-PSMA treatment. The OS advantage was also observed after multivariable adjustment (p&lt;0.01). Conclusions: Real-world evidence suggests that Lu-PSMA therapy provides significantly better PFS and OS outcomes in taxane-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment and should therefore considered as an early mCRPC treatment. A B Characteristic N Overall N = 269 1 Lu-PSMA, N = 29 (11%) 1 ARPI, N = 152 (57%) 1 p-value 2 Docetaxel, N = 88 (33%) 1 p-value 2 Age at metastatic disease, years 256 71 (65, 77) 74 (69, 79) 72 (66, 77) 0.055 68 (62, 73) &lt;0.001 Age at mCRPC, years 167 72 (67, 79) 76 (73, 83) 74 (68, 79) 0.083 69 (64, 75) &lt;0.001 PSA at mCRPC, ng/ml 133 17 (6, 47) 23 (9, 82) 18 (5, 47) 0.2 12 (4, 40) 0.091 Systemic treatment lines for mCRPC 269 3 (2, 4) 2 (1, 2) 3 (2, 4) &lt;0.001 3 (3, 5) &lt;0.001 Received cycles 139 3 (2, 6) 3 (2, 5) 4 (2, 6) 0.2 PSA response, % 26 23 (4, 62) 20 (11, 30) 17 (0, 90) 0.9 41 (17, 62) 0.3 ECOG at mCRPC 87 0.13 0.017 0 40 (46%) 4 (24%) 17 (45%) 19 (59%) 1-2 47 (54%) 13 (76%) 21 (55%) 13 (41%) Cardiovascular disease 171 64 (37%) 9 (50%) 33 (34%) 0.2 22 (39%) 0.4 Gleason score 8-10 234 165 (71%) 16 (62%) 89 (69%) 0.5 60 (76%) 0.2 Local therapy 269 112 (42%) 12 (41%) 52 (34%) 0.5 48 (55%) 0.2 De Novo metastatic disease 259 140 (54%) 15 (54%) 86 (59%) 0.6 39 (45%) 0.4 High volume mHSPC 104 55 (53%) 6 (67%) 35 (54%) 0.7 14 (47%) 0.5 Metastatic sites at mCRPC 110 0.8 0.4 M1a 13 (12%) 2 (11%) 5 (10%) 6 (15%) M1b 91 (83%) 15 (79%) 42 (84%) 34 (83%) M1c 6 (5.5%) 2 (11%) 3 (6.0%) 1 (2.4%)