²²⁵ Ac-PSMA-617/ ¹⁷⁷ Lu-PSMA-617 Tandem Therapy of Metastatic Castration-Resistant Prostate Cancer: Pilot Experience

Ziel/Aim Up to 30 % of patients with PSMA-positive mCRPC never respond, or develop resistance to ¹⁷⁷Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter ²²⁵Ac showed promise in the mCRPC setting, but may cause severe or persistent xerostomia, and substantially impair patients’ quality-of-life. We hypothesized that when ¹⁷⁷Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity ²²⁵Ac-PSMA ligand plus a unreduced activity of the beta-emitting radioligand may enhance efficacy while minimizing xerostomia severity.

Methodik/Methods Retrospective analysis of pilot experience with 1 course of ²²⁵Ac-PSMA-617/¹⁷⁷Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to ¹⁷⁷Lu-PSMA-617 monotherapy. This cohort had late-/end-stage disease with high baseline PSA concentration (median 215 ng/mL), heavy pre-treatment (prior abiraterone, enzalutamide, or both, and prior ¹⁷⁷LuPRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100 %; prior docetaxel, cabazitaxel or both in 13/20 patients, 65 %), and frequent ECOG performance status of 2 (8/20 patients, 40 %).

Ergebnisse/Results Median administered activities were ²²⁵Ac-PSMA-617, 5.3 (1.5–7.9) MBq and ¹⁷⁷Lu-PSMA-617, 6.9 (5.0–11.6) GBq. Subsequent maintenance therapy in case of significant response was performed with ¹⁷⁷Lu-PSMA-617 monotherapy (median of 1 treatment cycle; 0-5). After a median of 22 (14–63) wks’ follow-up, 13/20 patients (65 %) had as best biochemical response a PSA decline >50 %. Median (95 % CI) progression-free survival was 19 (12–25) wks, and overall survival, 48 (4-92) wks after tandem therapy administration. Grade 1 (very mild) xerostomia was reported in 8/20 patients (40 %), grade 2 (mild) dry mouth in 5/20 (25 %); no grade 3/4 xerostomia was noted.

Schlussfolgerungen/Conclusions Our results suggest that a single course of tandem therapy with low-activity ²²⁵Ac-PSMA-617/unreduced-activity ¹⁷⁷Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC, while minimizing xerostomia severity. Formal study of this combination is warranted.