Standard guidelines for treating metastatic prostate cancer are based on conventional imaging (CT/bone scan). The panel argues that PSMA PET-positive biochemical recurrence represents a different, earlier disease state. This necessitates new treatment paradigms, like definitive therapy durations, not covered by current guidelines.
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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.
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.
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.
For patients with oligometastatic disease who achieve a deep PSA response (e.g., to zero), oncologists consider finite treatment durations (e.g., 18-24 months) followed by observation. This "do less harm" approach challenges the standard of continuous therapy until progression, aiming for long-term treatment-free intervals.
Data from the CAPItello trial showed a significant number of patients with PTEN deficiency experienced radiological progression without a corresponding PSA increase. This challenges the standard reliance on PSA for monitoring in high-risk prostate cancer and suggests a need for more frequent, personalized imaging protocols to detect progression earlier.
Experts believe molecular tests like Decipher and PTEN status are superior to simply counting bone lesions for guiding treatment. While not yet standard practice for all decisions, this represents a significant shift towards using underlying tumor biology to determine therapy, like adding docetaxel.
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.