Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer

Abstract

Purpose: Actinium-225-labeled prostate-specific membrane antigen ([ 225 Ac]Ac-PSMA-617) is safe and effective in the treatment of metastatic castration-resistant prostate cancer (mCRPC). No study has specifically assessed its safety in patients with extensive skeletal metastases of mCRPC. We aimed to investigate the hematologic toxicity and efficacy of [ 225 Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC. Methods:We retrospectively reviewed the medical record of patients treated with [ 225 Ac]Ac-PSMA-617 for mCRPC. We included patients with a superscan pattern of skeletal metastases and those with 20 or more multifocal sites of skeletal metastases on baseline [ 68 Ga]Ga-PSMA-11 PET/CT. We reviewed the levels of hemoglobin, white blood cell (WBC), and platelet prior to each cycle of treatment and determined the presence of impaired bone marrow function at baseline and the grade of toxicity in the hematologic parameters induced by treatment. We evaluated the predictors of hematologic toxicity using binary logistic regression analysis. We also determined the presence of renal dysfunction before or during treatment. We assessed response to treatment using prostate-specific antigen response and the progression-free survival (PFS) and overall survival (OS).Results: A total of 106 patients were included. Skeletal metastasis was in the superscan pattern in 34 patients (32.1%) and multifocal in 72 patients (67.9%). The median treatment cycle was 4 (range = 1-9). Ninety-eight patients (92.5%) had abnormal baseline hematologic parameters. One patient had grade 4 thrombocytopenia. Grade 3 anemia, leukopenia, and thrombocytopenia were seen in 1 (0.9%), 3 (2.8%), and 2 (1.9%) patients, respectively. Age, the number of treatment cycles, and the presence of renal dysfunction were significant predictors of hematologic toxicity. Eighty-five patients (80.2%) achieved PSA response. The median PFS and OS of the study population were 14:00 (95%CI: 8.15-19.86) months and 15.0 (95%CI: 12.8-17.2) months, respectively.Conclusions: [ 225 Ac]Ac-PSMA-617 induces a good anti-tumor effect in about 80% of patients with extensive skeletal metastases of mCRPC with a rare incidence of severe hematologic toxicity. Age, number of treatment cycles, and the presence of renal dysfunction were significant risk factors for hematologic toxicity of [ 225 Ac]Ac-PSMA-617 therapy.

Response to RL‐225Ac in prostate cancer: Effect of prior treatment with RL‐177Lu: A systematic review of the literature

“…Of the included 14 series, 5 did not report outcomes of interest according to the prior status on 177Lu‐PSMA TRT 32–35 ; and, hence, also had the lowest scores on the Newcastle−Ottawa scale. However, of the studies that underwent quantitative analysis, the score ranged between 5 and 8 with most of them having good quality (e.g., scored 3 or 4 stars in the selection domain and 1 or 2 stars in comparability and 2 or 3 stars in the outcome category) (Table 7).…”

“…Of the included 14 series, 5 did not report outcomes of interest according to the prior status on 177Lu-PSMA TRT [32][33][34][35] ; and, hence, also had the lowest scores on the Newcastle−Ottawa scale.…”

A Treatment Paradigm Shift: Targeted Radionuclide Therapies for Metastatic Castrate Resistant Prostate Cancer

“…In a retrospective study of patients treated with 225 Ac PSMA-617, 106 patients were found to have either multifocal (≥20) skeletal metastases (n = 72, 67.9%), or a diffuse pattern of axial skeletal involvement with or without appendicular skeletal involvement (i.e., superscan pattern) on 68 Ga PSMA-11. Eighty-five of the 106 patients (80.2%) treated with 225 Ac PSMA-617 achieved a PSA response of ≥50% and had only rare hematologic toxicity with renal dysfunction being a significant risk factor [ 55 ]. As 225 Ac/ 177 Lu-PSMA radiopharmaceuticals have different benefits and risks, small trials have also incorporated a “tandem” therapy strategy with small doses of 225 Ac-PSMA being administered together with 177 Lu-PSMA and with promising results [ 56 ].…”

A Treatment Paradigm Shift: Targeted Radionuclide Therapies for Metastatic Castrate Resistant Prostate Cancer

“…In retrospective study of patient's treated with 225 Ac PSMA-617, 106 patients were found to have either multifocal (≥ 20) skeletal metastases (n=72, 67.9%), or a diffuse pattern of axial skeletal involvement with or without appendicular skeletal involvement (i.e., superscan pattern) on 68 Ga PSMA-11. Eighty-five of the 106 patients (80.2%) treated with 225 Ac PSMA-617 achieved a PSA response of ≥50% and had only rare hematologic toxicity with renal dysfunction being a significant risk factor [49]. As 225 Ac/ 177 Lu-PSMA radiopharmaceuticals have different benefits and risks, small trials have also incorporated a "tandem" therapy strategy with small doses of 225 Ac-PSMA being administered together with 177 Lu-PSMA and with promising results [50].…”