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.

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.

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).

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.

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.

The highly anticipated PROTEUS trial is testing a new drug combination against a control arm of ADT plus placebo for prostatectomy patients. This design is controversial because ADT is not standard care in this setting, raising concerns that a positive result could be driven by a suboptimal control arm.

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.

Designing a randomized trial to compare surgery versus systemic therapy alone is nearly impossible. A previous attempt, the SPARE study, failed to recruit because clinicians and patients already had strong pre-existing opinions on the best course of action, a bias that persists today.

The trial's principal investigator initially designed a control arm of prostatectomy alone. However, to maintain blinding and prevent patients from dropping out over a multi-year follow-up, a compromise was made to use ADT plus placebo, highlighting the pragmatic trade-offs required in large-scale clinical trials.