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.
Related Insights
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.
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.
Radioligand therapy has a unique toxicity profile, described as 'the gift that keeps on giving,' where side effects can worsen even after the treatment course is complete. This contrasts with chemotherapy like docetaxel, where a patient's quality of life often rebounds and improves once the drug is stopped.
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.
The common practice of switching from one ARPI to another upon disease progression is now considered ineffective for most patients. With the advent of proven alternatives like chemotherapy and lutetium, using an "ARPI switch" as the sole control arm in clinical trials is no longer ethically or scientifically sound.
The PR21 trial showed better overall survival for docetaxel followed by Lutetium, despite similar progression-free survival. The likely reason is not drug superiority but patient behavior: a higher percentage of patients complete the second therapy when starting with chemo, highlighting how treatment fatigue significantly impacts survival.
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.
A practical method to monitor radioligand therapy is a post-treatment SPECT scan. Since the therapeutic agent is radioactive, a simple planar scan about 24 hours after injection can visually confirm where the drug was delivered. This provides real-time feedback, beyond PSA levels, to potentially adapt treatment.
Three 2025 trials (AMPLITUDE, PSMA-addition, CAPItello) introduced personalized therapy for metastatic hormone-sensitive prostate cancer. However, significant benefits were confined to narrow subgroups, like BRCA-mutated patients. This suggests future success depends on even more stringent patient selection, not broader application of targeted agents.
The PSMA edition trial's fixed six-cycle Lutetium regimen, designed nearly a decade ago, is now seen as suboptimal. This illustrates how the long duration of clinical trials means their design may not reflect the latest scientific understanding (e.g., adaptive dosing) by the time results are published and debated.