Leveraging Beta and Alpha Emitters in Metastatic CRPC Management

In a conversation with CancerNetwork^® at the American Urological Association (AUA) 2025 Annual Meeting, Scott T. Tagawa, MD, MS, FASCO, FACP, highlighted the properties of lutetium Lu 177 (¹⁷⁷Lu) and how they may demonstrate benefit compared with other isotopes among patients with metastatic castration-resistant prostate cancer (CRPC). He spoke in the context of a clinical trial in progress presentation he gave that focused on the phase 3 ProstACT GLOBAL study (NCT04876651) evaluating ¹⁷⁷Lu-rosopatamab (TLX591) with standard of care vs standard of care alone among those with metastatic CRPC.

According to Tagawa, a professor of Medicine and Urology at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center, beta emitters like 177Lu may offer advantages such as built-in prostate-specific membrane antigen (PSMA) imaging and visibility based on its gamma emission. However, he characterized this gamma emission as a potential disadvantage, as those near someone treated with a beta emitter may be at risk of exposure to excess radiation.

Transcript:

Lutetium 177 is a beta emitter, the majority of which can kill cells. It’s relatively weak but can travel through many cells. It can go [across] mm. It also has some gamma emission, so it’s relatively easy to see. A therapeutic dose of lutetium also has good gamma emission; similar to a bone scan, we can see where it lands. Whether it’s good or bad, we can see where it lands, and we use that for dosimetry if we want to [and] as quality control to see where it is. [It has] a built-in PSMA imaging agent with each cycle. That’s one of the advantages of lutetium 177.

A disadvantage of lutetium 177 is the gamma shift. If I had it in me, you could get [exposed to] some of that. [For] someone close, especially for the first couple of days [after treatment], or with the small molecules treated in the urine, that could be dangerous. We haven’t seen anything ever go wrong, but that is it is a risk with lutetium 177.

There are other beta emitters that have less gamma emission and can travel over a longer range, such as yttrium-90, for instance. The main comparison that is not standard of care, except for radium, but moving into clinical trials and starting in some phase 3 trials, is alpha emitters. Probably the one in the prostate cancer world with the most data is actinium-225, which emits 4 alphas. It has a little bit of gamma, but they’re small, short-lived daughters; only very sophisticated imaging and technology are able to pick them up. That higher linear energy transfer, or potency, can overcome resistance as far as we know. Clearly, it’s true in the lab; we think that’s going to be true in patients. If someone is more refractory, an alpha [emitter] or any type of cell surface-targeting [agent] with a more potent payload has a higher chance of killing that tumor cell.

Reference

Tagawa S, Agarwal N, Cade D, Sartor O. ProstACT GLOBAL: A phase 3 study of 177Lu-rosptamab plus standard of care vs. standard of care alone in patients with metastatic castration-resistant prostate cancer. Presented at the American Urological Association (AUA) 2025 Annual Meeting; April 26-29, 2025; Las Vegas, NV.