225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience

• DOI: 10.1007/s00259-019-04612-0
• Publication Date: 2019-11-22T14:02:55Z
• Authors: Fadi Khreish; Niklas Ebert; Martin Ries; Stephan Maus; Florian Rosar; Hendrik Bohnenberger; Tobias Stemler; Matthias Saar; Mark Bartholomä; Samer Ezziddin
• Keywords: Actinium; Male; Dipeptides; Prostate-Specific Antigen; 3. Good health; Heterocyclic Compounds, 1-Ring; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Humans; Radiopharmaceuticals; Retrospective Studies

Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (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 against mCRPC but may cause severe and/or persistent xerostomia, which may 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 full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity.We retrospectively analyzed 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-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%).Median (minimum-maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20.Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-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.