For the roughly 300,000 men diagnosed annually with prostate cancer in the United States alone, the sequencing of treatments has long been dictated by disease stage and prior chemotherapy exposure. A comprehensive review now consolidates mounting trial evidence suggesting that lutetium-177-PSMA-617 radioligand therapy need not wait until the disease has exhausted multiple lines of treatment — a shift with potentially significant implications for long-term outcomes.
The review synthesizes findings across six major clinical trials spanning the full prostate cancer continuum. In metastatic castration-resistant prostate cancer, the VISION and TheraP trials established regulatory approval, while PSMAfore extended eligibility to taxane-naive patients and the ENZA-p combination trial demonstrated an overall survival advantage when lutetium-177-PSMA-617 was paired with enzalutamide versus enzalutamide alone. Moving earlier still, the Phase III PSMAddition trial showed improved radiographic progression-free survival when the radioligand was added to standard androgen deprivation therapy plus an androgen receptor pathway inhibitor in metastatic hormone-sensitive disease. In oligometastatic settings, the BULLSEYE and LUNAR trials suggest the approach may delay the need for androgen deprivation therapy entirely, potentially sparing patients its well-documented metabolic and cardiovascular side effects. The biological rationale for earlier deployment centers on higher and more homogeneous PSMA receptor expression in treatment-naive tumors, lower overall burden, and better-preserved bone marrow tolerance.
This synthesis arrives at a meaningful inflection point in oncology. Radioligand therapy's migration from last-resort to earlier-line treatment mirrors the historical arc of immune checkpoint inhibitors in other cancers — a pattern that often yields compounding survival benefits. However, several caveats demand attention. Many supporting trials are Phase II, with overall survival data still maturing. Progression-free survival, while encouraging, does not always translate to extended life. The next frontier involves next-generation radionuclides — actinium-225 and terbium-161 — which may address lutetium-177's radiobiological limitations, particularly in heterogeneous or radioresistant disease. Assessed overall, this review is confirmatory and synthesizing rather than paradigm-breaking on its own, but it maps a trajectory that clinicians and patients navigating treatment decisions will find increasingly consequential.