Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) holds promise as an innovative treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The WARMTH study, the largest investigation of its kind, showed the significant anti-tumour efficacy of 225Ac-PSMA RLT in mCRPC patients, establishing it as a viable therapy option following prior lines of approved agents. While xerostomia is a common side effect, severe bone marrow and renal toxicity are less frequently observed adverse events.
Most patients with metastatic castration-resistant prostate cancer (mCRPC) exhibit progressively rising levels of prostate-specific antigen (PSA) and widespread disease dissemination. Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) stands as a promising novel treatment for these patients. Given that 225Ac is an alpha emitter, it is anticipated to offer improved efficacy and fewer adverse effects compared to beta-emitters like Lutetium-177 (177Lu). This article reports the safety and anti-tumour activity of 225Ac-PSMA RLT in a large cohort of mCRPC patients, treated at multiple centres worldwide.1
Methods
The WARMTH Act study included patients treated at seven centres in Australia, India, Germany, and South Africa. The study pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, 177Lu PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival (OS) and progression-free survival (PFS).
Findings
This study included 488 men with mCRPC who received a median of two cycles of 225Ac-PSMA RLT. The mean age of these patients was 68.1 years, with a median baseline PSA of 169.5 ng/ml. Previous lines of treatment included docetaxel (66%), cabazitaxel (21%), abiraterone (39%), enzalutamide (39%), 177Lu-PSMA RLT (32%), and radium-223 dichloride (4%).
After a median follow-up of nine months, median OS was 15.5 months and median PFS was 7.9 months. Information regarding treatment-induced xerostomia was available in 347 (71%) of the 488 patients, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. Importantly, all patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade ≥3 anaemia occurred in 13% of patients, leukopenia in 4%, thrombocytopenia in 7%, and renal toxicity in 5%. No serious adverse events or treatment-related deaths were recorded.
Conclusions
This study shows that 225Ac-PSMA RLT yields substantial anti-tumour effects in patients with mCRPC and offers a viable therapeutic option for patients who have undergone previous lines of approved agents. Notably, while xerostomia is a common side effect, severe bone marrow and renal toxicity are rare occurrences with this treatment.1
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