First Clinical Results for PSMA-Targeted α-Therapy Using 225Ac-PSMA-I&T in Advanced-mCRPC Patients

J Nucl Med. 2021 May 10;62(5):669-674. doi: 10.2967/jnumed.120.251017. Epub 2020 Oct 2.

Abstract

Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using 225Ac-PSMA imaging and therapy (I&T). Methods: Fourteen patients receiving 225Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior 177Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Results: Thirty-four cycles of 225Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior 177Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after 177Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Conclusion: Our first clinical data for TAT using 225Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on 225Ac-PSMA-617 TAT.

Keywords: 225Ac and 177Lu; PSMA; metastatic castration-resistant prostate cancer; radioligand therapy; targeted α-therapy.

MeSH terms

  • Actinium / therapeutic use*
  • Antigens, Surface / metabolism*
  • Beta Particles / therapeutic use*
  • Glutamate Carboxypeptidase II / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasm Metastasis
  • Prostatic Neoplasms, Castration-Resistant / diagnostic imaging*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Prostatic Neoplasms, Castration-Resistant / radiotherapy*
  • Retrospective Studies
  • Treatment Outcome

Substances

  • Actinium-225
  • Antigens, Surface
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II
  • Actinium