KEY POINTS
- PROTEUS randomized more than 2,100 patients with high-risk localized prostate cancer to perioperative ADT plus apalutamide or ADT alone around radical prostatectomy, with more than five years of follow-up.
- Apalutamide increased pathological complete response or minimal residual disease from 1.0% to 8.9% and improved five-year metastasis-free survival when events detected by conventional imaging or PSMA PET were combined (78.2% vs 73.5%; HR 0.80).
- When metastasis-free survival was assessed using conventional imaging alone—the endpoint currently validated as a surrogate for overall survival—the difference was not statistically significant (HR 0.84, 95% CI 0.67–1.07). An overall survival benefit has not been demonstrated.
- The editorial emphasizes that PROTEUS enrolled a lower-risk population than the non-metastatic STAMPEDE trials: conventional-imaging N1 disease was present in 12.3% versus 39.2%, and clinical T3–T4 disease in 35.5% versus 92.3%, respectively.
- ENZARAD enrolled a population more similar to PROTEUS and also failed to improve conventional imaging-defined metastasis-free survival with androgen receptor pathway intensification (HR 0.88, 95% CI 0.67–1.15).
- Approximately 22 patients needed perioperative apalutamide to prevent one composite metastasis-free survival event at five years. PSA-free survival with testosterone recovery was only 29.5% versus 26.1% (HR 0.83), indicating that most patients still experienced recurrence or did not remain disease-free after hormonal recovery.
- The authors caution that perioperative intensification may expose many patients sequentially to prostatectomy, radiotherapy, ADT, and an androgen receptor pathway inhibitor. They advocate genomic classifiers and multimodal artificial intelligence to identify patients most likely to benefit and note that management after recurrence following one year of perioperative therapy remains undefined.
CLINICAL TAKEAWAY
PROTEUS does not yet establish perioperative apalutamide as routine treatment for every patient with high-risk localized prostate cancer undergoing prostatectomy. The observed benefit was modest and endpoint-dependent, while mature conventional imaging-defined MFS, overall survival, quality-of-life consequences, and better risk selection remain essential.