ESTRO welcomes the publication of the PROTEUS trial, which provides important prospective data on the management of high-risk localized and locally-advanced prostate cancer. The study confirms that adding the androgen receptor pathway inhibitor (ARPI) apalutamide to androgen-deprivation therapy (ADT) in the perioperative setting improves PSMA PET-based metastasis-free survival by 5% in absolute numbers for patients undergoing radical prostatectomy. Metastasis-free survival as assessed by conventional imaging was not improved, nor was overall survival. These findings align with existing evidence from definitive radiotherapy trials, reaffirming that some high-risk prostate cancer patients benefit from systemic treatment intensification.

The clinical implementation of these results merits careful contextualization. Currently, perioperative ADT is not recommended as standard practice, as it has historically not demonstrated a survival benefit over radical prostatectomy alone. The PROTEUS trial unfortunately lacked a surgery-alone control arm. Since perioperative ADT is not routinely offered in standard clinical practice, this raises a fundamental question: to which specific patient population should this intensified combination of ADT and apalutamide actually be offered, especially when weighed against the major increase in adverse events?

The trial highlights the persistent challenge of achieving long-term disease control with a surgery-first approach in this specific high-risk population. The data show that the 'freedom from disease' rate at 4 years remains modest, at 21.9% in the apalutamide arm and 18.3% in the placebo arm. Consequently, a significant proportion of patients ultimately required post-operative radiotherapy as part of a multimodal strategy.

These outcomes objectively underscore that for the vast majority of high-risk patients, local surgery alone—even with 12 months of intensified systemic therapy—is not definitive. Multimodality treatment, prominently including radiotherapy, remains a clinical reality for these patients.

This reinforces the necessity of shared decision-making. Patients should be counseled that an upfront, non-invasive organ-preserving strategy based on definitive radiotherapy combined with systemic therapy is a robust, guideline-recommended treatment strategy. By opting for primary radiotherapy, patients may avoid the compounded functional and physical burden of sequential local treatments (surgery followed by salvage radiotherapy) while benefiting from the same principles of systemic intensification.

As the therapeutic landscape advances, ESTRO continues to advocate for multidisciplinary tumor boards to ensure that every patient finds the most effective and tolerable pathway tailored to their individual disease profile and personal preferences.

Link to the trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2603878

Piet Ost, on behalf of the ESTRO Focus Group on Urology
Barbara Jereczek-Fossa, ESTRO President
Matthias Guckenberger, ESTRO Past-President
Carmen Rubio Rodriguez, ESTRO President-elect