Chronic kidney disease after 225Ac-PSMA617 therapy in patients with metastatic prostate cancer

Targeted radionuclide therapies (TRNT) are novel cancer treatments that deliver radiation selectively to cancer cells and the immediate tumor microenvironment. These agents consist of radiation-emitting radionuclides conjugated with monoclonal antibodies, peptides, or small molecules, each of which are able to specifically target tumor-associated antigens and hence allow for delivery of radiation directly, and almost exclusively, to tumor cells. The radiation emitted by these radionuclide particles causes DNA damage, triggering cancer cell death. Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostatic cancer, compared with the low levels of expression seen in a variety of tissue, including normal prostate and kidneys.1 Even higher levels are seen in metastatic and castration-resistant disease, allowing for targeted therapy. Radionuclide agents targeting PSMA include alpha (e.g., actinium-225) and beta emitters (e.g., lutetium-177). Alpha particle emissions like actinium-225 (225Ac) are more effective in targeted killing of tumor cells compared with beta emitters, due to greater energy generated, coupled with shorter path length.2 Unfortunately, kidney toxicity may result from tubular nuclide accumulation, intrinsic affinity of actinium for the kidney, and low-level kidney PSMA expression.2,3,S1 As seen in animal models, the multiple alpha particles generated in the decay chain of 225Ac, termed daughter nuclides, can accumulate in the kidney and lead to a progressive nephropathy.4 Promising therapeutic efficacy has been demonstrated with 225Ac-PSMA617 in patients with metastatic castration-resistant prostate cancer (mCRPC).5,S2 There are few data, however, on clinical renal toxicity associated with 225Ac-PSMA617. We report our experience with 225Ac-PSMA617 therapy in 2 patients with mCRPC who received these novel agents and developed progressive kidney disease.