AbstractPurpose:Metastatic castration-resistant prostate cancer has limited treatment options and a poor prognosis. Recently, prostate-specific membrane antigen (PSMA)-targeted alpha-particle therapy agents using actinium-225 (225Ac) have shown promising results in prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent 89ZrDFO-YS5, and the radioimmunotherapy agent 225AcMacropa-PEG4-YS5, in disseminated prostate cancer tumors.Experimental Design:Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with 89ZrDFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of 225AcMacropa-PEG4-YS5.Results:Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from 225AcMacropa-PEG4-YS5 in microtumors compared with surrounding liver tissues, although in larger lesions (>1 mm diameter), the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with a uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.Conclusions:Our findings highlight that 225AcMacropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.See related commentary by Patel et al., p. 2847
Bidkar et al. (Tue,) studied this question.