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.

Beyond primary endpoints, a clinically meaningful benefit of the neoadjuvant apalutamide regimen was a 30% reduction in the need for postoperative radiotherapy. The investigator highlights this as avoiding 'double local therapy' (surgery plus radiation), a scenario often linked to increased long-term urinary toxicity for patients.

The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.

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).

Johnson & Johnson's data for its drug Erlita doesn't just offer an incremental improvement; it challenges the century-old practice of immediate radical prostatectomy for high-risk prostate cancer. Integrating pharmaceutical treatment before and after surgery could fundamentally shift the treatment paradigm from a purely surgical approach to a multidisciplinary one.

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.

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.