Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts

Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with (177)lutetium ((177)Lu)-PSMA-617 represented a pivotal step forward and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include (177)Lu, (131)iodide ((131)I), and (67)copper ((67)Cu). Targeted alpha emitters potentially include (225)actinium ((225)Ac), (227)thorium ((227)Th), and (212)lead ((212)Pb). Phase III trials are underway with both (177)Lu-PSMA-617 and (177)Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with (225)Ac-J591 but additional data are need to launch a phase III. Data are promising with (225)Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.