What a New Study Reveals About Actinium-225 PSMA Therapy and Metastatic Castration-Resistant Prostate Cancer

For patients with metastatic castration-resistant prostate cancer (mCRPC), emerging research suggests that actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) may have a significant impact in reducing prostate-specific antigen (PSA) levels and bolstering progression-free and overall survival rates.

For the retrospective, multicenter study, recently published in Lancet Oncology, researchers examined data from 488 patients with histopathologically confirmed adenocarcinoma of the prostate who received at least one cycle of 225Ac-PSMA RLT (8 MBq, intravenous) for mCRPC.

(Editor’s note: This article has been adapted with permission from our sister publication Urology Times.)

At a median follow-up of nine months, the median overall survival was 15.5 months and the median progression-free survival was 7.9 months. Nearly three-fourths (73 percent) of patients had any PSA decline and 57 percent of patients had a PSA decline of at least 50 percent.

“To our knowledge, this is the largest investigation of the antitumor effect and toxicity of 225Ac-PSMA RLT in mCRPC,” wrote lead study author Mike M. Sathekge, M.D., who is affiliated with the Department of Nuclear Medicine at the University of Pretoria in Pretoria, South Africa, and colleagues. “225Ac-PSMA radioligand therapy has substantial antitumor effects in mCRPC … Prospective trials are needed to validate the safety and survival benefits of 225Ac-PSMA RLT in patients with mCRPC.”

Patients had a mean age of 68.1 years (range, 37-90) and a median baseline PSA of 169.5 ng/mL (interquartile range, 34.6-519.8). ECOG performance status was as follows: 0 (25 percent), 1 (40 percent), 2 (16 percent), 3 (9 percent), 4 (3 percent), and not available (8 percent).

For the 363 patients for whom International Society of Urological Pathology grade groups were available, the groups were grade 1 (6 percent), grade 2 (10 percent), grade 3 (13 percent), grade 4 (25 percent), and grade 5 (47 percent). Metastases in patients included bone (89 percent), lymph node (72 percent), visceral (20 percent), and peritoneal (2 percent). Prior treatments included docetaxel (66 percent), cabazitaxel (21 percent), abiraterone (39 percent), enzalutamide (39 percent), 177Lu-PSMA RLT (32 percent), and radium-223 dichloride (4 percent).

Patients received a median of two treatment cycles (IQR, 2-4).

Regarding safety, the authors noted that among 347 patients with available xerostomia data, 68 percent (n = 236) experienced treatment-induced xerostomia following their first cycle of 225Ac-PSMA RLT. Further, xerostomia was reported in all patients who received more than 7 cycles of 225Ac-PSMA RLT.

Other toxicities of note were grade ≥3 anemia in 13% of the 488 patients, grade ≥3 leukopenia in 4 percent, grade ≥3 thrombocytopenia in 7 percent, and grade ≥3 renal toxicity in 5 percent. The authors reported no serious adverse events or treatment-related deaths.

“The results of this international multicenter study provide the strongest evidence to date supporting the antitumor activity and safety of 225Ac-PSMA RLT for mCRPC treatment,” maintained Sathekge and colleagues.

“The anti-tumor effect of 225Ac-PSMA RLT in mCRPC is influenced by several factors, including previous treatment with taxane-based chemotherapies and the pattern of mCRPC metastases. These factors should be considered in selecting patients for 225Ac-PSMA RLT, especially considering the current limitation in 225Ac supply and the prevalence of xerostomia induced by this therapy.”

Reference

1. Sathekge MM, Lawal IO, Bal, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicenter, retrospective study. Lancet Oncol. 2024 Jan 10:S1470-2045(23)00638-1. doi:10.1016/ S1470-2045(23)00638-1

(Editor's note: For additional content on prostate cancer imaging, click here.)