Why Radioligand Therapy May Belong Earlier

After the FDA’s 2025 expanded approval of Pluvicto (lutetium Lu-177 vipivotide tetraxetan) for PSMA-positive metastatic castration-resistant prostate cancer prior to chemotherapy, PSMA-targeted radioligand therapy is now being used earlier in advanced disease.   Investigators are increasingly asking whether these agents may deliver even greater benefit when moved earlier in the disease course.  Dr. Daniel Spratt, Chairman and Professor of Radiation Oncology at University Hospitals (UH) Seidman Cancer Center argues that earlier use — potentially without prolonged androgen deprivation therapy — may improve depth of response, reduce toxicity, and open the door to curative-intent strategies.

 

  • Dr. Spratt believes PSMA-targeted radioligand therapy may be most effective when used earlier, before tumors develop extensive heterogeneity and treatment resistance.

  • Long-term androgen deprivation therapy can suppress PSMA expression, potentially limiting the ability of radioligand therapy to target all cancer cells.

  • Earlier-stage use may allow fewer radioligand therapy cycles, with lower risk of marrow suppression, xerostomia, and ocular dryness.

  • Head-to-head data in advanced disease show markedly better patient-reported quality of life with radioligand therapy compared with chemotherapy, even when overall survival is similar.

As prostate cancer treatment becomes increasingly precise, clinicians are reexamining long-standing assumptions about sequencing — particularly the routine use of prolonged androgen deprivation therapy (ADT) in high-risk localized disease.

According to Daniel Spratt, Chairman of Radiation Oncology at  Case Western Reserve University and a leader of clinical trials at UH Seidman Cancer Center, radioligand therapy combined with highly targeted external-beam radiation may offer a more biologically rational and potentially curative approach — especially when used early. “This is true precision radiation oncology,” Spratt said. “We’re taking men with high-risk, newly diagnosed localized prostate cancer — sometimes even with lymph node involvement — and combining ultra-hypofractionated radiation to the prostate with just a few doses of lutetium PSMA radioligand therapy. Together we’re seeing unprecedented results.”

The Limitations of Hormone Therapy as Backbone

For decades, standard management for high-risk localized disease has relied heavily on years of ADT combined with surgery or radiation. While effective at suppressing disease, Spratt argues that ADT may unintentionally blunt the effectiveness of newer targeted approaches.  “Hormone therapy is basically putting the cancer to sleep so it stops expressing as much PSMA,” he explained. “That means when you give radioligand therapy, you’re primarily targeting cells that have already developed resistance to hormone therapy, while other cancer cells are essentially hidden.”

This biologic interaction may help explain why radioligand therapy can produce dramatic responses in advanced disease yet often fails to eradicate all tumor clones.  “If you ever stop hormone therapy, those untreated areas can still exist,” Spratt said.

Why Earlier May Be Better

Spratt believes the optimal window for radioligand therapy is before extensive clonal heterogeneity and treatment resistance develop.  “Almost always, the biggest bang for our buck with our most effective therapies is when they’re moved earlier in the course of disease,” he said.  This concept is driving trials in men with high-risk localized or node-positive disease who appear non-metastatic on imaging but are known to have a high likelihood of microscopic systemic spread.

The rationale:

  • SBRT delivers a curative-intent dose to dominant local disease

  • Radioligand therapy targets occult micrometastatic cells throughout the body

Neither modality alone is sufficient in this setting, but together they may be complementary.  “Radioligand therapy can’t always give enough dose to cure a large primary tumor, but it may be very good at treating small microscopic areas we can’t see,” Spratt said. “External radiation can give a very high dose to a few areas. The combination is what makes this powerful.”

Dosing, Toxicity, and Quality-of-Life: Another Argument for Earlier Use

Beyond biology, dosing and tolerability are central to the case for earlier radioligand therapy.  “Every therapy is really about how much you give,” Spratt said. “Earlier in the course of disease, patients tend to have less cancer and not widely metastatic disease. So we’re often only giving maybe two or three doses of radioligand therapy.”  By contrast, men treated in very advanced stages commonly receive six cycles — double or triple the exposure.

Higher cumulative dosing is associated with increased risk of:

  • Transient bone marrow suppression

  • Xerostomia from salivary gland PSMA uptake

  • Dry eyes related to lacrimal gland expression

“These side effects become more of a concern when you give more and more doses,” Spratt noted. “That’s another potential advantage of using these agents earlier.”

Radioligand therapy has also been compared head-to-head with chemotherapy in advanced prostate cancer. “Patient-reported quality of life is dramatically superior with radioligand therapy compared with chemotherapy — even when patients receive six doses,” Spratt said. “Overall survival may be similar, but the way patients feel is markedly improved with radioligand therapy.”

Toward Reducing or Eliminating Long-Term ADT

A central question now being tested: can radioligand therapy replace prolonged ADT in selected patients?  “More and more, we’re thinking that the optimal timing of radioligand therapy — when safe and appropriate — is actually without hormone therapy,” Spratt said. “That’s where I think the future is headed.”

If successful, this strategy could reduce exposure to ADT-related toxicities while improving depth and durability of response.   While radioligand therapy is largely viewed as life-prolonging,  Spratt sees a different goal in earlier-stage patients.  “This isn’t just palliative. This is to cure a patient — to never need any more therapy in their life,” he said. “That, to me, is even more impactful than where we’re currently using these agents.”

Practical Implications for Clinicians

  • Consider whether high-risk localized or node-positive patients may be candidates for trials evaluating early radioligand therapy

  • Reassess automatic reliance on prolonged ADT as the backbone of therapy

  • Begin thinking about sequencing based on tumor biology and target expression, not just stage

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.