The WARMTH^[*]-initiated multicentre retrospective study investigated the efficacy and safety of ²²⁵Ac-PSMA radioligand therapy (RLT) in treating metastatic castration-resistant prostate cancer (mCRPC). This study included 488 men from Australia, India, Germany, and South Africa, aged between 37 and 90. Most patients had previously undergone multiple treatments, including chemotherapy, androgen-axis-receptor inhibitors, or ¹⁷⁷Lu-PSMA RLT.

The findings show that 73% of the patients experienced some PSA decline after at least one cycle of ²²⁵Ac-PSMA RLT, with 57% showing a decline of 50% or more. Despite common side effects like xerostomia and bone marrow toxicities (with a notable prevalence of impaired bone marrow observed before treatment initiation), the therapy was generally well-tolerated, even in patients with pre-existing conditions.

With the study being retrospective, ²²⁵Ac-PSMA RLT was frequently administered as a last-line intervention when all other options had been exhausted and proven ineffective.

A significant association was found between a PSA decline of at least 50%, absence of prior exposure to specific treatments, lack of certain metastases, and absence of anaemia at the initiation of ²²⁵Ac-PSMA RLT with extended both progression-free and overall survival. However, the number of treatment cycles did not correlate with improved progression-free survival or overall survival.

In conclusion, ²²⁵Ac-PSMA RLT demonstrated significant antitumor effects in mCRPC, even in individuals with compromised bone marrow and renal function. The impact of previous treatment history and metastatic burden on time to death or disease progression suggests that patients with a comparatively lower disease burden may derive greater benefit from ²²⁵Ac-PSMA RLT.

Our clinic has an established practice of offering our patients with a corresponding disease profile a combination therapy of 1 + 2 (one ²²⁵Ac-PSMA + two ¹⁷⁷Lu-PSMA cycles). 

^[*] WARMTH – World Association of Radiopharmaceutical & Molecular THerapy