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.
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.
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.
There is long-term data showing that adding hormone therapy to radiation can be curative for some prostate cancer patients. However, for surgery, historical and recent trials like PROTEUS have not demonstrated that perioperative hormone therapy adds a curative benefit, suggesting its role is more cytostatic in that context.
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.
The standard practice of using rising PSA to trigger early salvage radiotherapy after surgery is complicated by the PROTEUS protocol's neoadjuvant hormone therapy. This approach muddies the interpretation of biochemical recurrence, making it difficult for clinicians to know when or if to intervene with salvage treatment, potentially leading to worse outcomes.
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.
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.