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Despite meeting its primary endpoint, the PROTEUS trial provides no validated biomarkers to identify which patients actually benefit from the intensified therapy. This lack of a predictive signature means applying the results in the clinic amounts to uniform escalation, likely overtreating many patients for an uncertain benefit, making it difficult to implement.
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Unlike in breast or bladder cancer, the significant improvement in pathologic response in the PROTEUS trial did not translate to a similarly impressive benefit in metastasis-free survival. This disconnect suggests that eliminating tumor in the prostate specimen is not a reliable surrogate for long-term outcomes in this disease setting.
PROTEUS changed its primary endpoint mid-study to include PSMA PET-detected metastasis. While this led to a statistically positive result, it raises concerns that the benefit is merely earlier detection (lead-time bias) rather than a true improvement in curing micrometastatic disease and improving overall survival.
Despite emerging trial data, clinicians are not yet ready to change therapy based on ctDNA positivity alone. Key concerns cited include the absence of a proven survival benefit from early intervention, the potential to use future treatment lines prematurely, and overall feasibility. The consensus is that while promising, the technology is not yet ready for routine clinical decision-making.
The PROTEUS trial used ADT plus surgery as its control, not surgery alone. This design is controversial because many patients choose surgery specifically to avoid systemic therapies like ADT. This complicates the interpretation of results and reflects a disconnect from real-world patient motivations.
Early neoadjuvant trials in the 1990s failed to show clinical benefit because they included many low-risk patients and used less potent hormonal therapies. The PROTEUS trial's success was built on learning from this history by strictly enrolling high-risk patients and using a powerful androgen receptor pathway inhibitor (ARPI).
When looking only at the original endpoint of metastasis-free survival by conventional imaging, the PROTEUS trial was not positive. This result is consistent with the negative ENZERAD trial, which tested a similar drug combination with radiation instead of surgery. This cross-trial consistency suggests adding an ARPI may not provide a substantial benefit in this setting.
Despite acknowledging that a one-size-fits-all treatment duration is suboptimal, the expert consensus is to follow the study protocol. This conservative, evidence-based approach prevails due to the absence of validated biomarkers, like ctDNA, to safely guide treatment de-escalation for individual patients.
The Proteus trial's requirement of 2,000 patients highlights a fundamental issue in adjuvant therapy: to prove a modest benefit, a vast number of patients who may already be cured by surgery must be treated. This means many participants endure toxic therapy with no personal benefit, raising ethical concerns.
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.
Event-free survival rates at four years were concerningly low in both arms of the PROTEUS trial. This suggests the trial may have enrolled a population with a very high baseline risk of recurrence, potentially including patients with pre-existing micrometastatic disease, which could limit the study's applicability to a broader high-risk population.