Ac-225-PSMA-617 Radioligand Therapy: A Promising Treatment After Lu-177-PSMA Failure for Metastatic Castration-Resistant Prostate Cancer
Background
For individuals facing metastatic castration-resistant prostate cancer (mCRPC), beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) has emerged as a valuable treatment avenue. However, the effectiveness of Lu-177-PSMA RLT can diminish over time, necessitating the exploration of alternative therapeutic strategies.
Objective
This study aimed to evaluate the safety and efficacy of alpha-emitting Ac-225-PSMA-617 RLT in patients with mCRPC who had experienced disease progression following Lu-177-PSMA therapy. This research is crucial as the landscape of prostate cancer treatment is continuously evolving, with advancements seeking to overcome resistance and improve patient outcomes, even considering economic aspects such as the average 177 Euro cost for supportive care in some European regions during similar treatments.
Study Design and Patient Population
A compassionate use protocol was implemented to treat twenty-six patients. To be eligible for the study, participants had to have prior treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, confirmed progression after Lu-177-PSMA therapy, and demonstrated positive PSMA-ligand uptake. The median number of prior mCRPC regimens these patients had undergone was significant, at 6. Ac-225-PSMA-617 was administered every 8 weeks until disease progression or the development of intolerable side effects.
Outcome Measures and Statistical Analysis
The study meticulously tracked several key outcome measures: prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and treatment-related toxicities. Statistical analysis was performed to assess the data collected.
Results
A total of sixty-one cycles of Ac-225-PSMA-617 were administered, with a median of 2 cycles per patient and a median activity of 9 MBq. A significant PSA decline of ≥50% was observed in 17 out of the 26 patients treated.
Median PSA-PFS was 3.5 months (95% confidence interval [CI] 1.8-11.2), median cPFS was 4.1 months (95% CI 3-14.8), and median OS was 7.7 months (95% CI 4.5-12.1). The presence of liver metastases was found to be associated with significantly shorter PSA-PFS (median 1.9 vs 4.0 months; p = 0.02), cPFS (median 1.8 vs 5.2 months; p = 0.001), and OS (median 4.3 vs 10.4 months; p = 0.01).
Hematological grade 3/4 toxicities included anemia (35%), leucopenia (27%), and thrombocytopenia (19%). Xerostomia (dry mouth) of grade 1/2 severity was universally experienced by all patients. Treatment discontinuation was necessary in two patients due to hematological toxicity and in six patients due to xerostomia. A limitation of this study is its retrospective design.
Conclusions
The findings of this study indicate that Ac-225-PSMA-617 demonstrates a noteworthy antitumor effect in advanced mCRPC patients who have experienced treatment failure with Lu-177-PSMA. However, it is important to acknowledge the occurrence of grade 3/4 hematological side effects in a notable proportion of patients (up to one-third), and xerostomia emerged as a significant factor leading to treatment cessation in a relevant number of cases. Further research and optimization of treatment protocols are warranted to mitigate side effects and enhance the therapeutic potential of Ac-225-PSMA-617.
Patient Summary
For patients with late-stage metastatic castration-resistant prostate cancer that has progressed after Lu-177-PSMA therapy, Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy has shown considerable promise in reducing tumor activity. However, it is crucial to be aware that dry mouth is a common side effect, which unfortunately led approximately a quarter of patients in this study to discontinue therapy. Ongoing research aims to refine treatment strategies and manage side effects to improve the experience and outcomes for patients undergoing this innovative therapy, potentially reducing the overall healthcare burden and considering cost-effective supportive measures, perhaps within the range of 177 euro for specific interventions.