Refining Radioligands: Combinations, Payloads, and New Targets

As radioligand therapy moves toward earlier lines of treatment, the field is entering a new phase—one focused not just on whether these drugs work, but how best to deploy them.    “Radioligands aren’t going to live in isolation,” said Dr. Daniel Spratt, Chairman and Professor of Radiation Oncology at University Hospitals (UH) Seidman Cancer Center. “The future is about building smarter combinations, choosing the right payload for the right setting, and being honest about what we still don’t know—especially when it comes to long-term side effects.”

  • Combinations: Radioligands are increasingly being paired with external beam radiation, androgen receptor–targeted therapies, immunotherapy, and other systemic agents to deepen responses—particularly in lesions or disease sites that may receive suboptimal radioligand dosing alone.

  • Payloads (Alpha vs Beta): Ongoing research is exploring when beta-emitting isotopes may be sufficient versus when higher–linear energy transfer alpha emitters could offer greater tumor kill, as well as how dosing and cycle number should change when radioligands move earlier in disease.

  • Targets Beyond PSMA: While PSMA remains the dominant target in prostate cancer, multiple new targets are under investigation, raising the possibility of sequential or dual-target radioligand strategies tailored to tumor biology and resistance mechanisms.

  • Side Effects and Unknowns: Earlier-line use and lower cumulative dosing may reduce marrow suppression and other toxicities, but long-term effects—particularly with alpha emitters and combination regimens—remain incompletely understood.

Clinicians are now interrogating optimal combinations, radioactive payload selection, and new molecular targets while asking important unanswered questions about toxicity.

Using Radioligands with Targeted External Beam Radiation

“One of the biggest synergies is going to be targeted external beam radiation with radioligand therapy,” explained Dr. Daniel Spratt Chairman and Professor of Radiation Oncology at CWRU and University Hospitals (UH) Seidman Cancer Center. “You can functionally do spots or metastases or areas of the body that the radioligand can’t get quite enough dosing. You can supplement that with targeted external beam radiation. I think that’s going to probably be one of the biggest combinations or most powerful combinations.”

Radioligand therapy delivers radioactive payloads systemically to cancer cells expressing specific molecular targets. While this approach can reach disease throughout the body, some lesions may receive suboptimal dose. Using focal external beam radiation to intensify treatment to selected sites offers a rational way to improve local control without substantially increasing whole-body toxicity.

Not all combinations, however, appear equally promising. Chemotherapy, for example, raises concerns about overlapping bone marrow suppression. “I’m not sure chemotherapy is going to be a great combination. I think that might end up being too toxic to the bone marrow,” Spratt noted, underscoring the importance of pairing radioligands with partners that have complementary rather than additive toxicities.

Alpha Vs Beta Radioligand Payloads

Another major area of investigation centers on the radioactive payload itself. Most clinically used radioligands employ beta-emitting radionuclides, such as lutetium-177, which release moderate-energy radiation that travels a short distance. These agents have demonstrated consistent efficacy and relatively predictable safety profiles.

In contrast, alpha emitters deliver extremely high-energy radiation over a very short range. “Think of betas as spreading further but not quite as powerful,” Spratt said, “and alphas as very short range—they won’t hit a lot, but they’re very powerful.” Because of this potency, alphas may be less forgiving from a toxicity standpoint, though they generate excitement for their potential to produce deep tumor responses. Trials are now exploring combinations of alpha- and beta-emitting radioligands, as well as sequencing strategies, to balance potency and safety.

Beyond PMSA Targeting

Beyond payloads, investigators are also expanding the list of molecular targets used to guide radioligands. PSMA remains the dominant target, but others are gaining momentum. “Another very promising target is HLK2,” Spratt said, describing it as closely related to PSA and more highly expressed in prostate cancer cells than in most normal tissues. Additional targets such as STEAP1 and STEAP2 are also under study.

Importantly, these targets are not necessarily drivers of tumor growth. “It’s not something that the cancer is using for growth necessarily,” Spratt explained. “It’s something that is on the cancer cell or in it or being secreted by it that is selective to cancer compared to your healthy tissue.” The goal is to improve the therapeutic ratio—maximizing tumor dose while minimizing off-target exposure.

Dosing and Mitigating Future Side Effects

Side effects remain an essential part of the conversation. Common issues include fatigue, bone marrow suppression, dry mouth, and renal exposure because many radioligands are excreted through the urinary system. Dose and scheduling are therefore central considerations, particularly as interest grows in moving radioligand therapy earlier in the disease course.

“If we believe that a patient will benefit from a systemic treatment, the question is what is going to provide at least equal efficacy with the best quality of life,” Spratt said. He noted that PSMA-targeted radioligand therapy may offer a more favorable quality-of-life profile than both chemotherapy and long-term hormone therapy. Still, important unknowns persist. “There are some concerns moving it earlier… what will happen 10 years later, 15 years later, 20 years later? Could this type of radiation cause cancer?”

For that reason, he emphasized restraint with cumulative dosing. “If you are using it earlier, we really need to be using it as just two or three doses, not six or more doses.”

Taken together, radioligand therapy is entering a more sophisticated phase—one defined by optimization rather than mere adoption. While enthusiasm remains high, clinicians recognize that many questions are unanswered.  The next chapter will focus not only on expanding access to radioligands, but on refining how, when, and in whom they are used to deliver durable benefit with acceptable long-term risk.

PLEASE NOTE:  “Early Radioligand Therapy” –  either in localized high risk prostate cancer or mCRPC that has not yet failed ARPI is not currently an approved use by the FDA and should only be administered within the context of a clinical trial to eligible patients.

–

Read More