High-Risk Localized/Locally Advanced Prostate Cancer: Perioperative Systemic Therapy With Radical Prostatectomy

Authored by Natalia Gandur, published on 2026-05-26 22:56:01.0

The clinical objective of this algorithm is to support patient selection and postoperative management decisions for selected patients with high-risk localized or locally advanced prostate cancer who are being considered for radical prostatectomy with perioperative systemic therapy. The algorithm incorporates emerging data from the PROTEUS trial while avoiding extrapolation beyond the currently available evidence.

  1. High-risk localized / locally advanced prostate cancer being considered for radical prostatectomy
    • Confirm staging and selection
      PSA Grade Group MRI PSMA PET cT/cN status ECOG Life expectancy Surgical fitness Preferred staging may include PSMA PET, though supporting perioperative trial data were based primarily on conventional imaging.
      • Metastatic disease on conventional imaging?
        • Yes → Metastatic prostate cancer pathway
        • No → Continue
          • Multidisciplinary Team discussion of curative-intent options
            RP + ePLND vs RT + long-term ADT ± abiraterone vs clinical trial / PROTEUS-informed approach
            • Appropriate candidate for perioperative systemic therapy + RP?
              • No → Standard local therapy / RT-based pathway
              • Yes → Continue
                • PROTEUS-style perioperative systemic therapy (ADT + apalutamide) for patients with non-metastatic disease on conventional imaging (Pending final ASCO interpretation / data maturity)
                  Perioperative ADT+ARPI around RP is an emerging strategy; publicly available evidence has historically been strongest for improved pathologic response rather than definitive long-term outcomes, and guideline endorsement remains limited/conditional. This node is appropriately labeled as pending/maturing evidence and best aligned with a clinical-trial or carefully selected-use posture.
                  • Radical prostatectomy + ePLND
                    • Postoperative reassessment (Pathology + PSA + recovery + toxicity)
                      • Undetectable PSA + favorable pathology (surveillance with PSA monitoring)
                        Observation with PSA surveillance after RP is standard when PSA is undetectable and there are no adverse features warranting early intervention.
                        • Follow-up & monitoring (PSA, toxicity, bone/metabolic health, urinary/sexual function, recurrence)
                      • Undetectable PSA + adverse pathology (observation with close PSA monitoring favored; consider early salvage RT at PSA rise)
                        Multiple randomized trials and meta-analyses support early salvage RT (initiated at low PSA) as the preferred strategy over routine adjuvant RT for many patients with adverse pathology and undetectable PSA, with ongoing individualization for very high-risk features.
                        • Follow-up & monitoring (PSA, toxicity, bone/metabolic health, urinary/sexual function, recurrence)
                      • pN1 disease with undetectable PSA (observation or individualized consideration of RT ± ADT; routine adjuvant therapy not universally recommended)
                        Post-RP pN1 management is supported by guideline recommendations and mostly non-randomized evidence; ADT+RT is commonly favored for higher nodal burden/adverse features, while observation may be reasonable for carefully selected limited-node patients with undetectable PSA. The evidence base is heterogeneous and evolving, so this node is inherently preference- and risk-stratified.
                        • Follow-up & monitoring (PSA, toxicity, bone/metabolic health, urinary/sexual function, recurrence)
                      • PSA persistence after RP (failure to achieve undetectable PSA) (early salvage therapy ± systemic intensification / clinical trial)
                        Detectable/persistent PSA after RP warrants confirmation, consideration of restaging (including PSMA PET), and prompt salvage therapy; addition of ADT to salvage RT is supported by randomized trials in appropriate patients. The role of further systemic intensification beyond ADT in this setting remains evolving and is often trial-based.
                        • Follow-up & monitoring (PSA, toxicity, bone/metabolic health, urinary/sexual function, recurrence)
                      • pN1 disease with detectable PSA (salvage RT + systemic therapy consideration)
                        • Follow-up & monitoring (PSA, toxicity, bone/metabolic health, urinary/sexual function, recurrence)
  2. IMPORTANT
    PROTEUS eligibility was based on conventional imaging (CT/bone scan). Some conventionally non-metastatic patients may have been PSMA PET-positive.
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