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.
Contrary to common belief, centralized radiology review isn't always superior. In blinded trials, local radiologists with specialist knowledge and clinical context can be as, or more, accurate. The PROTEUS trial's investigator-assessed Metastasis-Free Survival (MFS) showed an even stronger treatment effect (HR 0.74) than the blinded central review (HR 0.80).
When PSMA PET became the standard of care for detecting prostate cancer metastasis, the PROTEUS trial amended its protocol to include it alongside conventional imaging. The trial's positive Metastasis-Free Survival (MFS) result was driven by this composite endpoint, as the analysis using conventional imaging alone was not statistically significant.
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.
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 used two pathologic endpoints. The investigator suggests Residual Cancer Burden (RCB), which measures cellularity, is a more meaningful reflection of response than just residual tumor size. The RCB endpoint showed a much larger treatment effect (30% vs. 11%) compared to the tumor size endpoint (9% vs. 1%).