Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with ²²⁵Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control

Abstract

The aim of this evaluation was to identify the first indicators of efficacy for Ac-labeled prostate-specific membrane antigen (PSMA)-617 therapy in a retrospectively analyzed group of patients. Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. A positive response for surrogate parameters demonstrates remarkable antitumor activity for Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused additional administrations and was in the same dimension as nonresponse; this finding indicates that further modifications of the treatment regimen with regard to side effects might be necessary to further enhance the therapeutic range.

Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

“…It has already been demonstrated that RLT with PSMA‐617 labelled with the alpha emitter 225 Ac ( t 1/2 ≈9.9 days) may overcome this radioresistance . Recent clinical studies have reported that targeted alpha therapy (TAT) using 225 Ac‐ and 213 Bi‐labelled PSMA ligands is a promising treatment of mCRPC . Despite the great efficacy, their limited supply, the toxicity in salivary glands of 225 Ac, and the short half‐life of 213 Bi ( t 1/2 ≈46 minutes) warrant to explore other alpha‐emitting radionuclides for PSMA‐RLT.…”

Targeted alpha therapy with bismuth‐213 and actinium‐225: Meeting future demand

“…225 Ac has so far been used in conjunction with specific carrier molecules to target leukemia, glioma, neuroendocrine tumors, as well as prostate cancer . A summary of the clinical experience obtained to date is given in Table .…”

“…A summary of the clinical experience obtained to date is given in Table . The clinical tests in previous studies were carried out with 225 Ac produced, quality‐controlled, and supplied by JRC Karlsruhe.…”

“…Patients of the Pretoria cohort had often received little or no prior treatment because of limited access to healthcare among the poorest segments of the South African population . Generally, the patients who received alpha therapy as an early treatment option showed a better response than those who had previously received a wide range of conventional treatment options, including hormone therapy, chemotherapy or radiotherapy with the beta‐emitting nuclide 177 Lu . In a direct comparison between 213 Bi and 225 Ac, the latter is found to be at least as effective as the former (at the maximum tolerable dose), but at a much lower cost …”

“…3 The radionuclides for targeted alpha therapy discussed in this paper are highlighted in red summary of the clinical experience obtained to date is given in Table 2. The clinical tests in previous studies 14,[19][20][21][22][23] were carried out with 225 Ac produced, qualitycontrolled, and supplied by JRC Karlsruhe. As shown in the table, the most extensive clinical experience to date has been gained with more than 300 prostate cancer patients treated with 225 Ac-labeled PSMA-617.…”