Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

Abstract

The use of ²²⁵Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with ¹⁷⁷Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT in ¹⁷⁷Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [⁶⁸Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT, with at least one [²²⁵Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.

Keywords: 225Ac and 177Lu; PSMA radioligand therapy; biochemical response; efficacy; metastatic castration-resistant prostate cancer; molecular imaging response; toxicity.

Figure 1

Waterfall plots of individual changes in (A): PSA serum value; (B): MTV; (C): TLP. Red: progressive disease (PD). Blue: stable disease (SD). Green: partial remission (PR). * Appearance of new metastases.

Figure 2

[⁶⁸Ga]Ga-PSMA-11 PET/CT images of two mCRPC patients (A,B) at baseline and after two cycles of [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT showing partial remission (exemplary: liver metastases, orange arrow; bone metastases, green arrow).

Figure 3

Kaplan–Meier curves of (A): PSA-based progression-free survival of the entire cohort; (B): overall survival of the entire cohort; (C): overall survival stratified by molecular imaging response (green: partial remission (PR); red: progressive disease (PD) or stable disease (SD)).

Figure 4

Graphical illustration of CTCAE grades for thrombocytopenia, leukocytopenia, anemia, renal function impairment and xerostomia at baseline (upper row) and after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT with at least one [²²⁵Ac]Ac-PSMA-617 augmentation (lower row).