Radioligand Therapy Doesn’t Need to Be Risk-Free—It Needs to Be Worth It

Last month’s mRNA neoantigen vaccine data announcement, paired with the recent FDA approval of daraxonrasib and advances in radioligand therapy, have some commentators calling this year one of the most consequential ever for cancer treatment.¹⁻³ Replacing broad-spectrum treatments with highly targeted therapies is transforming the patient experience. However, this shift toward precision oncology comes with heightened volatility: as more targeted therapies enter clinical trials, high-profile failures can make a promising field appear far more precarious than it actually is.

As we analyze the promise and pitfalls of this new field, the right question to ask about a new cancer treatment is not simply whether it carries risk. Every effective cancer treatment does. The question is whether the benefits outweigh those risks, and how they compare with the alternatives available to patients.

Evaluating Benefits and Risks in Radioligand Therapy

For most patients receiving radioligand therapy or other targeted treatments, those alternatives can include treatments that carry substantial toxicity. Chemotherapy, for instance - which can harm healthy cells as well as cancerous ones - can cause hair loss, neuropathy, severe nausea, marrow damage and other side effects that can significantly affect quality of life.⁴ That context matters when we evaluate new treatments.

Approved Radioligand Therapies Are Transforming Cancer Care

Consider the radioligand therapies already approved and in use today. Peptide receptor radionuclide therapy using lutetium DOTATATE, used to treat neuroendocrine tumors, outperforms every other approved drug in that category, while being remarkably well tolerated.⁵ It has changed the standard of care for many patients. I’ve even heard patients say they forgot they had cancer after receiving it, a remarkable thing to hear from someone with incurable cancer.

PSMA radioligand therapy has similarly changed the treatment landscape for patients with advanced prostate cancer.⁶ In patients who have exhausted all other options, it can prolong survival with limited side effects. Although PSMA radioligand therapy has side effects (i.e. dry mouth and fatigue), it is a better tolerated option compared to chemotherapy for most patients.⁷ Furthermore, there are new RLT products in development, which may offer an improved side effect profile for prostate cancer patients. Importantly, these treatments are not an endless cycle of therapy: many patients receive a set of treatments and then have a meaningful break before their next cancer therapy.

Drug Design Shapes Radioligand Therapy Safety

None of this means toxicity isn’t real, or that every radioligand therapy in development will clear the bar these have. The relevant question is not whether radioligand therapies carry risk, but whether the benefits of a therapy justify those risks, and that answer cannot be determined by the isotope or target alone. A variety of factors determine a drug’s safety profile, from the target, to the targeting molecule, the linker, and the chelator, which all affect the way the drug distributes in the body. Two therapies aimed at the same biological target can have meaningfully different safety and efficacy profiles because of how they are constructed and how normal tissue is exposed to radiation.

Comparing Alpha- and Beta-Emitting Radioligand Therapies

That distinction is particularly important as we look at newer therapies using alpha particles.⁸ Alpha particles are certainly more effective at killing cancer cells than the beta particles used in approved lutetium-based therapies, but they also can cause more toxicity. The question, then, is not simply which particle is more ‘effective’. It is whether the added efficacy is worth the added risk for a particular patient.

And this is where the conversation around radioligand therapy can become too simplistic. It is tempting to say that one isotope is “safer” and another is “more dangerous.” Biology is not that simple. The same isotope can behave very differently depending on the molecule it is attached to, how that molecule distributes through the body and which patients receive it. You can have one construct that is more toxic without being more effective, and another that delivers greater efficacy without the same increase in toxicity.

Clinical Trials Define the Therapeutic Window

This is exactly what clinical trials are for. They allow us to better understand the tradeoff between efficacy and toxicity. When a therapy in development shows a toxicity signal serious enough that a company pulls back or drops the product completely, that is not evidence that the entire field has failed. It’s evidence that the clinical trial process is doing what it’s supposed to do. Some drugs will not have an acceptable therapeutic window, and they should not move forward. Others will.

The Future of Radioligand Therapy in Precision Oncology

FDA-approved radioligand therapies have already transformed cancer care. Lutetium DOTATATE and PSMA Radioligand Therapy are effective treatments that many patients tolerate remarkably well. Their success is precisely why researchers are now asking what comes next: new targets, new molecules, new isotopes and new ways to treat patients whose cancers have stopped responding to existing therapies.

As precision oncology advances, new treatment options are changing what patients can expect from a hard diagnosis. We should evaluate those treatments with the same standard we apply to every cancer therapy: Is it effective? What are the risks? And, most importantly, how do those risks compare with what patients would otherwise face?

Dr. Thomas Hope is a Professor in the Department of Radiology and Biomedical Imaging at UCSF and a nationally recognized expert in molecular imaging and radioligand therapy. He serves as Vice Chair of Clinical Operations and Strategy and as Director of Theranostics. His research focuses on developing and translating novel imaging agents and targeted therapies, particularly for prostate cancer and neuroendocrine tumors. Dr. Hope helped lead the development of Ga-68 PSMA-11, which became the first PSMA-targeted PET imaging agent approved by the FDA. He also leads UCSF’s clinical programs in PSMA radioligand therapy and peptide receptor radionuclide therapy.

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