The effectiveness of radioligand therapy is counterintuitive: as tumors shrink and PSMA binding sites decrease, less radiation is delivered to the cancer. The VISION trial showed the first two doses delivered more radiation to the tumor than the subsequent four, questioning the value of a fixed, prolonged treatment schedule.

Unlike traditional chemotherapy, radioligand therapy's toxicity may be inversely correlated with tumor volume. In low-burden disease, fewer cancer cells act as a 'sink' for the drug, potentially leading to higher radiation exposure and side effects in healthy, PSMA-expressing tissues like salivary glands.

The PSMA Addition study, adding lutetium in metastatic hormone-sensitive prostate cancer, showed an RPFS benefit. However, initial data suggested adverse quality of life scores. Upcoming results on pain and skeletal events are critical to determine if the toxicity profile undermines its clinical utility in this earlier disease setting.

After years of successfully intensifying hormonal therapy, the focus in prostate cancer is shifting toward de-intensification. Researchers are exploring intermittent therapy for top responders and developing non-hormonal approaches like radioligands to spare patients the chronic, life-altering side effects of permanent castration.

The PANFA trial's investigation of Actinium-225, an alpha-emitter, signals the next wave of radioligand therapy. Unlike the current beta-emitter standard Lutetium, alpha-emitters offer a shorter range but more potent cell-killing effect, positioning them as a promising treatment for patients who have already progressed on existing therapies.

Lutetium faces criticism for its fixed 6-cycle regimen, which may be suboptimal as the PSMA target diminishes with ADT. However, this critique is rarely applied to other drugs like PARP inhibitors, which are given until progression. This highlights a double standard and the tension between using a fixed regimen for regulatory approval versus finding the optimal dose in practice.

Even when an ARPI is no longer effective as a standalone therapy, continuing it may be beneficial. By maintaining pressure on the androgen receptor pathway, the drug can upregulate downstream targets like PSMA, potentially enhancing the efficacy of subsequent PSMA-targeted therapies like radioligands or ADCs.

Clinicians may be biased towards lutetium-PSMA because it causes significant PSA drops, which radium-223 does not. This observable metric may not reflect superior overall efficacy, as radium's survival benefit is proven and it may even have unique synergistic potential with drugs like enzalutamide through different biological pathways.

While Lutetium shows promise in hormone-sensitive prostate cancer, experts raise concerns about potential late-effect toxicities for patients surviving many years. This contrasts with docetaxel, where toxicity is acute and resolves after treatment, highlighting an unknown long-term risk-benefit profile for new radioligand therapies.