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.
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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.
The negative ANSA-RAD trial, when contrasted with the positive STAMPEDE trial, demonstrates that patient selection is paramount in adjuvant therapy. The difference in outcomes was driven by risk definition, not the drug. This reinforces that "negative" trials are clinically vital for defining which patient populations do not benefit, preventing widespread overtreatment.
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.
For an older patient population, the ultimate goal in prostate cancer treatment might not be a traditional cure, but rather turning it into a quiescent, chronic disease manageable with well-tolerated therapy, similar to HIV. This reframes success as long-term control until a patient dies of other causes.
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.
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.
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 IMbark trial demonstrated that an ARPI (enzalutamide), either alone or with ADT, outperformed ADT monotherapy in high-risk patients. This pivotal finding raises the question of whether giving ADT alone in any setting, such as with radiation for localized disease, is now an outdated and inferior approach.