A new European Urology Oncology Priority Article places one of the most closely watched prostate cancer studies of 2026 under the microscope: the Phase 3 PROTEUS trial of perioperative apalutamide plus androgen-deprivation therapy (ADT) in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.
Published on July 1, the editorial, “PROTEUS Trial the Day After: Practice Changing or Premature Escalation?”, reflects the central question now facing the prostate cancer community. The results are clearly positive. The more difficult issue is whether they are sufficient to support routine treatment intensification for all patients who meet the study’s high-risk criteria.
A Trial That Shifted the Perioperative Conversation
For decades, radical prostatectomy has remained a central curative-intent treatment option for localized high-risk prostate cancer. However, the risk of recurrence remains substantial in patients with aggressive pathological features, nodal involvement, high Gleason grade, or locally advanced disease.
The PROTEUS trial tested whether earlier and more prolonged androgen-receptor pathway suppression could improve outcomes around surgery.
A total of 2,109 patients with high-risk localized or locally advanced prostate cancer were randomly assigned to receive either apalutamide plus ADT or placebo plus ADT before and after radical prostatectomy with pelvic lymph-node dissection. The study included six 28-day treatment cycles before surgery and six cycles after surgery.
The co-primary endpoints were pathological complete response or minimal residual disease and metastasis-free survival.
The Pathological Response Signal Was Hard to Ignore
The pathological findings were among the most striking results of the trial.
Pathological complete response or minimal residual disease was achieved in 8.9% of patients treated with apalutamide plus ADT, compared with 1.0% in the placebo-plus-ADT group. This translated into an odds ratio of 10.17 in favor of perioperative apalutamide.
For a disease in which complete eradication of tumour at prostatectomy has historically been uncommon following systemic treatment, this difference immediately drew attention.
The trial also reported lower rates of positive surgical margins in the intensified-treatment group, raising the possibility that preoperative systemic therapy may influence not only microscopic residual disease but also surgical pathology more broadly.
Still, pathological response is not the same as cure. The place of pathological complete response and minimal residual disease as reliable long-term surrogate endpoints in prostate cancer remains an important topic of debate.
Metastasis-Free Survival Gives the Study Clinical Weight
PROTEUS did not rely on pathology alone.
At five years, metastasis-free survival was 78.2% with apalutamide plus ADT and 73.5% with placebo plus ADT. The addition of apalutamide was associated with a 20% reduction in the risk of distant metastasis or death.
Event-free survival, time to subsequent treatment, and time to distant metastasis also favored the apalutamide-containing regimen.
The event-free survival findings were particularly notable. Median event-free survival was 57.1 months in the apalutamide group, compared with 38.4 months in the placebo group. Time to the first subsequent prostate cancer treatment was also prolonged, with median times of 74.2 months and 41.5 months, respectively.
These outcomes move the discussion beyond a pathological response signal. They indicate that perioperative apalutamide plus ADT can delay recurrence-related events and reduce the need for further local or systemic treatment in a population at considerable risk of relapse.
Why the Debate Is Not Settled
The European Urology Oncology editorial arrives at a crucial moment because PROTEUS raises questions that are larger than one regimen.
The trial compared apalutamide plus ADT with placebo plus ADT. It did not directly compare perioperative apalutamide plus ADT and surgery with radical prostatectomy alone in the main study population.
This distinction matters.
For many patients with high-risk disease, treatment decisions involve a choice between surgery-based and radiotherapy-based strategies, each with different patterns of systemic treatment, toxicity, follow-up, and salvage options. A positive comparison against placebo plus ADT does not automatically answer whether perioperative apalutamide should be integrated into every surgical treatment pathway.
The appropriate population for escalation also remains under discussion. High-risk prostate cancer is a broad category. It includes patients with markedly different risks of nodal involvement, biochemical recurrence, distant metastasis, and prostate cancer mortality.
Some patients may derive major benefit from earlier systemic intensification. Others may face additional treatment burden without the same absolute gain.
Imaging and Endpoints Matter
Another important feature of PROTEUS is its use of both conventional imaging and prostate-specific membrane antigen positron-emission tomography, or PSMA PET, in the metastasis-free survival analysis.
PSMA PET can identify metastatic disease earlier than conventional imaging in many patients. This improves staging precision but also complicates comparisons with older studies that relied primarily on computed tomography, magnetic resonance imaging, and bone scanning.
The definition of metastasis-free survival therefore matters. Earlier detection of metastatic disease may alter the timing of events, subsequent treatment decisions, and interpretation of outcomes across studies.
As PSMA PET becomes increasingly integrated into clinical practice, future trials will need to clarify how imaging modality affects endpoint interpretation and how results should be translated into day-to-day treatment decisions.
Toxicity Cannot Be Treated as a Secondary Question
The PROTEUS findings support a more intensive perioperative approach, but they also introduce additional exposure to systemic treatment before and after surgery.
Apalutamide plus ADT was associated with more adverse events than placebo plus ADT in the published trial. Treatment-related effects of androgen-receptor inhibition and prolonged androgen suppression may include fatigue, hot flashes, rash, falls, cardiovascular considerations, metabolic effects, sexual dysfunction, and effects on quality of life.
For patients receiving treatment with curative intent, these issues are not peripheral. The goal is not simply to delay recurrence, but to do so while preserving function and minimizing unnecessary harm.
This is particularly relevant for men whose disease may have been controlled with surgery alone or with later salvage treatment.
The Need for Better Patient Selection
The next phase of the PROTEUS conversation will likely focus on identifying which patients are most likely to benefit from perioperative treatment intensification.
Clinical stage, Gleason score, PSA level, nodal status, imaging findings, surgical pathology, genomic alterations, and molecular features may all help refine treatment selection.
The study includes planned biomarker analyses, and these may be especially important. A broadly positive Phase 3 trial can establish the value of a regimen at the population level. Biomarker work may determine whether its use can become more precise at the individual-patient level.
The challenge will be to avoid two extremes: withholding effective therapy from patients with the highest risk of recurrence, while also avoiding overtreatment in patients whose absolute benefit may be limited.
A New Benchmark, Not the Final Word
PROTEUS has created a new benchmark for perioperative systemic therapy in surgically treated high-risk prostate cancer. The pathological response, metastasis-free survival, event-free survival, and subsequent-treatment results are clinically meaningful and difficult to dismiss.
At the same time, the editorial’s title captures the caution now required: practice-changing or premature escalation?
The answer may depend less on whether the regimen works and more on how carefully the field defines the patients for whom earlier intensification is justified.
Sources: Heidegger IM, Mercinelli C, Marvaso G, et al. PROTEUS Trial the Day After: Practice Changing or Premature Escalation? European Urology Oncology. July 1, 2026. Taplin ME, Gleave M, Shore ND, et al. Perioperative Apalutamide in High-Risk Localized Prostate Cancer. New England Journal of Medicine. 2026.
Written by Nare Hovhannisyan, MD
Stay informed with more articles like this on OncoDaily