SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 333,830 new cases of prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention.
Background
Patients with high-risk localized prostate cancer and locally advanced prostate cancer remain at substantial risk for recurrence following definitive local therapy. Radical prostatectomy with pelvic lymph node dissection is a potentially curative treatment option. However, disease recurrence occurs in up to 50% of patients within five years of surgery. Long-term outcomes remain suboptimal despite advances in surgical techniques and patient selection.
The use of neoadjuvant systemic therapy before surgery is established in several solid tumors, but previous studies evaluating neoadjuvant approaches in prostate cancer have not resulted in changes to clinical practice. Earlier trials were limited by heterogeneous patient populations, including lower-risk disease, and by reliance on endpoints such as Prostate-Specific antigen (PSA) response rather than long-term oncologic outcomes.
Phase 2 studies investigating Androgen Receptor Pathway Inhibitors in the neoadjuvant setting demonstrated reductions in residual tumor burden and increased rates of pathological response, providing the rationale for larger randomized studies. Apalutamide (ERLEADA®) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.
The Phase 3 PROTEUS trial was designed to determine whether perioperative treatment with Apalutamide plus Androgen Deprivation Therapy (ADT) could improve pathological and long-term clinical outcomes in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.
Study Design and Patient Population
PROTEUS was a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled patients with newly diagnosed high-risk localized or locally advanced prostate cancer.
A total of 2,109 patients were randomized in a 1:1 ratio to receive either:
- Apalutamide 240 mg daily plus ADT (N=1,057), or
- Placebo plus ADT (N=1,052)
Treatment was administered for six 28-day cycles before surgery, followed by radical prostatectomy with pelvic lymph node dissection. After surgery, patients received an additional six cycles of their assigned treatment. A two-week treatment break was incorporated before surgery, followed by a four-week break after surgery before treatment resumed.
Eligible patients had high-risk localized or locally advanced disease based on histologic and clinical criteria, including PSA level and nodal status assessed by conventional imaging. The median age of enrolled patients was 66 years, and 95.8% had a Gleason score of 8 or higher. The median follow-up was 61.7 months.
Study Endpoints
The trial had two Primary endpoints:
- Pathological Complete Response (pCR) or minimal residual disease, defined as pathological Stage ypT2 or lower with residual tumor measuring no more than 5 mm in greatest dimension.
- Metastasis-Free Survival (MFS), assessed by Blinded Independent Central Review using conventional imaging and/or Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET).
Secondary endpoints included:
- Event-Free Survival (EFS)
- Time to first subsequent treatment
- Time to distant metastasis
- Safety
Exploratory analyses included assessment of residual cancer burden and investigator-assessed Metastasis-Free Survival.
Primary Endpoint: Pathological Response
The addition of Apalutamide to ADT resulted in higher rates of pathological Complete Response or minimal residual disease at the time of surgery.
Pathological Complete Response or minimal residual disease was achieved in 8.9% of patients receiving Apalutamide plus ADT versus 1.0% of patients receiving placebo plus ADT. This corresponded to an odds ratio of 10.17 (95% CI, 5.27–19.64; P<0.0001).
These findings indicate a substantially greater proportion of patients had limited or no residual tumor identified in the surgical specimen following neoadjuvant treatment with Apalutamide plus ADT.
Primary Endpoint: Metastasis-Free Survival (MFS)
The Second Primary endpoint, Metastasis-Free Survival, was also met.
Treatment with Apalutamide plus ADT was associated with a reduction in the risk of distant metastasis or death compared with placebo plus ADT (Hazard ratio: 0.80; 95% CI: 0.67–0.96; P=0.0169). At five years, MFS rates were 78.2% in the Apalutamide group and 73.5% in the placebo group. Median MFS was not reached in either treatment arm. Investigator-assessed MFS showed similar results, with a Hazard Ratio of 0.74 (95% CI, 0.62–0.87).
Secondary Efficacy Endpoints
All key secondary efficacy endpoints favored the Apalutamide-containing regimen.
Event-Free Survival (EFS) was prolonged with Apalutamide plus ADT (Hazard ratio: 0.71; 95% CI: 0.63–0.80; P<0.0001). Median EFS was 57.1 months with Apalutamide plus ADT versus 38.4 months with placebo plus ADT
The addition of Apalutamide delayed the need for additional local, regional, or systemic therapy, including re-initiation of ADT (Hazard Ratio: 0.65; 95% CI: 0.57–0.73; P<0.0001). Median time to first subsequent treatment was 74.2 months in the Apalutamide arm and 41.5 months in the placebo arm.
Time to distant metastasis also favored Apalutamide plus ADT (Hazard Ratio: 0.68; 95% CI: 0.55–0.83; P=0.0002). Median time to distant metastasis was not reached in either treatment group.
Residual Cancer Burden Analysis
Exploratory analyses evaluating residual cancer burden also demonstrated lower residual disease following treatment with Apalutamide. Minimal residual disease based on residual cancer burden criteria was observed in 30.6% of patients receiving Apalutamide plus ADT versus 11.7% of patients receiving placebo plus ADT. The odds ratio was 3.36 (95% CI, 2.67–4.23; P<0.0001). These findings support the association between intensified Androgen Receptor Pathway Inhibition and reduction in residual tumor burden at surgery.
Role of PSMA PET Imaging
PROTEUS incorporated both conventional imaging and PSMA PET imaging in the assessment of Metastasis-Free Survival. The inclusion of PSMA PET reflects changes in prostate cancer staging and recurrence assessment during the conduct of the trial. PSMA PET has greater sensitivity than conventional imaging, particularly at low PSA levels, and is increasingly incorporated into routine clinical practice. The study authors noted that increasing use of PSMA PET may influence assessment of disease recurrence and should be considered in future clinical trial designs evaluating localized prostate cancer.
Safety
The safety profile of Apalutamide plus ADT was consistent with previous studies of Apalutamide. Grade 3 or 4 treatment-emergent adverse events occurred in 39.6% of patients receiving apalutamide plus ADT and 31.0% of patients receiving placebo plus ADT. The difference was primarily attributable to a higher incidence of rash in the Apalutamide arm. Treatment discontinuation due to adverse events occurred in 7.4% of patients receiving Apalutamide and 2.7% of patients receiving placebo. No new safety signals were identified during the study.
Clinical Implications
PROTEUS is the first Phase 3 trial to demonstrate improvements in both pathological response and Metastasis-Free Survival with perioperative Androgen Receptor Pathway Inhibition in patients undergoing radical prostatectomy for high-risk localized or locally advanced prostate cancer.
Treatment with Apalutamide plus ADT before and after surgery resulted in higher rates of pathological Complete Response or minimal residual disease, improved Metastasis-Free Survival, prolonged Event-Free Survival, delayed need for subsequent treatment, and longer time to distant metastasis compared with ADT alone.
These findings provide evidence supporting perioperative treatment intensification with Apalutamide plus ADT in patients with high-risk localized or locally advanced prostate cancer who are candidates for radical prostatectomy.
Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study. Mary-Ellen Taplin M-E, Gleave M, Shore ND, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1)
