PROTEUS: Apalutamide plus ADT before and after RP cuts metastasis risk

Final analysis of the phase 3 PROTEUS trial (NCT03767244) demonstrated that 1 year of perioperative apalutamide (Erleada) plus androgen deprivation therapy (ADT) combined with radical prostatectomy (RP) significantly improved metastasis-free survival (MFS), pathological complete response (pCR) or minimal residual disease (MRD), event-free survival (EFS), and time to first subsequent therapy compared with placebo plus ADT with RP in patients with high-risk localized or locally advanced prostate cancer (HR-LPC).

Mary-Ellen Taplin, MD, FASCO, institute physician, chair of the Executive Committee for Clinical Research at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School in Boston, Massachusetts, presented the data at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. The results were simultaneously published in the New England Journal of Medicine.^1,2

Background and unmet need

Despite refinements in RP as a curative-intent treatment for patients with high-risk disease, more than half will relapse, incurring morbidity from subsequent therapy. Development of metastases carries a poor prognosis, with a median time from metastasis to death of 3 to 5 years.^3-6 The androgen receptor pathway inhibitor apalutamide is approved for metastatic castration-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer^7,8 and has shown favorable activity in the neoadjuvant setting in phase 2 trials.^9,10 PROTEUS was designed to determine whether 1 year of perioperative apalutamide plus ADT improves pathological response and long-term outcomes vs placebo plus ADT in this setting.

Trial design and patient population

PROTEUS is a randomized, double-blind, placebo-controlled phase 3 trial conducted across 184 sites in 18 countries. A total of 2109 patients with HR-LPC were randomly assigned 1:1 to apalutamide (240 mg once daily) plus ADT or placebo plus ADT, stratified by nodal stage (cN0 vs N1), Gleason score (7 vs 8-10), and region. Treatment was administered for 6 cycles neoadjuvantly (cycles 1-6) and 6 cycles adjuvantly (cycles 7-12), with a 2-week hold prior to RP and resumption 4 weeks postoperatively. Patients were randomly assigned from July 15, 2019, to June 30, 2022. A protocol amendment in April 2022 incorporated prostate-specific membrane antigen (PSMA)-PET into the MFS composite end point. A substudy evaluating apalutamide plus ADT plus RP vs RP alone is ongoing and was not reported at this analysis.

The trial had dual primary end points assessed by blinded independent central review (BICR): pCR/MRD—defined as organ-confined disease (ypT0 or tumor confined to the prostate [ypT2] or smaller, N0) with no tumor identified or minimal residual tumor of 5 mm or smaller—and MFS, defined as time to radiographic distant metastasis by conventional or PSMA-PET imaging, pathologic finding of distant metastasis, or death from any cause. Key secondary end points included EFS, time to first subsequent therapy, time to distant metastasis (TTDM), no evidence of disease at 4 years, MFS by conventional imaging only, and time to prostate-specific antigen (PSA)-free survival with testosterone recovery.

Baseline characteristics were well balanced between arms. Median age was 66 years (interquartile range, 62-71 in the apalutamide arm; 61-70 in the placebo arm), and more than 95% of patients in each arm had a Gleason score of 8 or higher. Median baseline PSA level was 14.4 ng/mL in the apalutamide arm vs 15.1 ng/mL in the placebo arm. Approximately 35% of patients in each arm had tumor stage T3 or higher at diagnosis, and 12% had N1 nodal disease. At the clinical cut-off of February 2, 2026, median follow-up was 61.7 months.

Primary end points met: pCR/MRD and MFS

The pCR/MRD rate at RP was 8.9% (94/1057) in the apalutamide arm vs 1.0% (10/1052) in the placebo arm, representing a 9-fold improvement (OR, 10.17; 95% CI, 5.27-19.64; P < .0001). More than half of the responses in the apalutamide arm were pCRs (5.1% ypT0 vs 0.4%). The exploratory residual cancer burden (RCB) end point—defined as prostate-confined disease with RCB of 0.25 cm³ or smaller—corroborated the pCR/MRD result, with rates of 30.6% vs 11.7% in the apalutamide and placebo arms, respectively (OR, 3.36; 95% CI, 2.67-4.23; P < .0001).

For the co-primary end point of MFS by conventional or PSMA-PET imaging by BICR, the apalutamide arm demonstrated a 20% reduction in the risk of metastasis or death (HR, 0.80; 95% CI, 0.67-0.96; P = .02). Investigator-assessed MFS was consistent with BICR results (HR, 0.74; 95% CI, 0.62-0.87; P = .0004).

"The pCR, MRD, and residual cancer burden all support better response for apalutamide and ADT compared to placebo and ADT," Taplin said. "More than half of the responses in the apalutamide cohort were [pathological complete responses]."

Key secondary end points

EFS—defined as time to biochemical failure, local or regional recurrence, distant metastasis, or death from any cause—was significantly improved with apalutamide plus ADT vs placebo plus ADT (HR, 0.71; 95% CI, 0.63-0.80; P < .0001), representing a 29% reduction in the risk of an oncologic event or death. Median EFS was 57.1 months in the apalutamide arm vs 38.4 months in the placebo arm.

Time to first subsequent therapy—encompassing local, regional, or systemic therapy including reinitiation of ADT—strongly favored the apalutamide arm (HR, 0.65; 95% CI, 0.57-0.73; P < .0001), with median time to first subsequent therapy of 74.2 months vs 41.5 months, a difference of nearly 3 years. Subsequent therapy events occurred in 42.4% of patients in the apalutamide arm vs 56.7% in the placebo arm. Rates of subsequent systemic therapy (26.7% vs 36.4%) and postoperative radiotherapy (13.0% vs 18.4%) were both lower in the apalutamide arm.

TTDM by conventional or PSMA-PET imaging was also significantly improved (HR, 0.68; 95% CI, 0.55-0.83; P = .0002), with 82.8% (95% CI, 80.0-85.2) of patients in the apalutamide arm free from distant metastasis at 5 years vs 76.2% (95% CI, 73.2-79.0) in the placebo arm. MFS by conventional imaging alone did not reach statistical significance (HR, 0.84; 95% CI, 0.67-1.07; P = .15), which Taplin attributed in part to the dilutional effect of PSMA-PET–detected metastases triggering subsequent therapy—thereby delaying the appearance of metastases on conventional imaging—in 70% of patients who underwent PSMA-PET imaging.

"The fact that 87% in the apalutamide and ADT cohort were without metastasis by conventional imaging at 5 years is a very positive outcome for these patients," Taplin said.

Testosterone recovery

Testosterone recovery was similar between arms. Among patients with testosterone recovery to 200 ng/dL or greater, 81.6% of patients in the apalutamide arm and 83.0% in the placebo arm achieved this threshold. Median time from end of treatment to testosterone recovery was 8.1 months in the apalutamide arm vs 6.6 months in the placebo arm. Taplin noted that 89% of participants in both arms recovered testosterone to 100 ng/dL or greater.

Safety

All-grade treatment-related adverse events (AEs) were similar between arms (95.2% with apalutamide plus ADT vs 93.8% with placebo plus ADT). Grade 3 or 4 treatment-related AEs were higher in the apalutamide arm (27.5% vs 18.9%), as were treatment-related AEs leading to dose reduction (11.2% vs 2.3%) and dose interruption (12.0% vs 4.4%). Treatment-related AEs leading to death occurred in 7 patients (0.7%) in the apalutamide arm vs 1 patient (0.1%) in the placebo arm. Taplin emphasized that 5 of the 7 deaths in the apalutamide arm were deemed related to surgery, and that after a protocol amendment requiring cardiovascular risk assessment and cardiology evaluation in higher-risk patients prior to enrollment and 1 month before RP, no further treatment-related deaths occurred in either arm.

Among treatment-emergent AEs (TEAEs) of special interest, skin rash was the only event occurring at a notably higher rate in the apalutamide arm (33.0% vs 15.3% all grades; 5.9% vs 0.3% grade 3 or higher). Other TEAEs of special interest, including falls (3.2% vs 2.8%), ischemic heart disease (2.4% vs 2.1%), nonpathological fracture (2.1% vs 1.8%), cerebrovascular disorders (0.8% vs 1.2%), and seizure (0.2% vs 0.1%), occurred at low and comparable rates between arms. Fatigue was common in both arms (27.7% vs 26.8%) and predominantly low grade.

"Apalutamide and ADT was well tolerated with no new safety signals," Taplin said.

Conclusions

In her concluding remarks, Taplin said PROTEUS is the largest therapeutic trial in localized high-risk prostate cancer and the first to demonstrate MFS benefit with perioperative systemic therapy in this setting. She characterized the results across pCR/MRD, MFS, EFS, and time to subsequent therapy as establishing a new standard of care. Future analyses will include the substudy comparing the PROTEUS regimen with RP alone, biomarker assessments, surgical outcomes, and correlation of major pathological response with MFS.

"PROTEUS has novel end points of major pathologic response and MFS measured both by conventional and PSMA-PET imaging," she said. "Compared to placebo [plus] ADT, apalutamide [plus] ADT showed 9 times more pCR/MRD, a 20% improved MFS, a 29% reduction in prostate cancer recurrence, and a 3-year improvement in time to subsequent therapy."

DISCLOSURES: Taplin reported disclosures related to Amgen, Astellas Pharma, AstraZeneca, Axis Medical Education, Blue Earth Diagnostics, Carden Jennings, DAVA Pharmaceuticals, Flare Therapeutics, Geode Therapeutics, GlaxoSmithKline, Interpublic GIS, Janssen-Ortho, Laekena, MJH Healthcare Holdings, LLC, Novartis, Pfizer, Physicians’ Education Resource, Research to Practice, UpToDate, BioNTech, the Advanced Prostate Cancer Society, the Prostate Cancer Foundation, and the South West Prostate Cancer Symposium.

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