For decades, perioperative systemic therapy has failed to improve long-term outcomes after radical prostatectomy in high-risk localized prostate cancer. The phase III PROTEUS trial may be the first to break that pattern. Presented as LBA1 during the Plenary Session at the 2026 ASCO Annual Meeting, the final analysis showed that adding apalutamide to androgen-deprivation therapy (ADT) before and after radical prostatectomy significantly improved both major pathologic response and metastasis-free survival in patients with high-risk localized or locally advanced prostate cancer.¹

Mary-Ellen Taplin, MD, FASCO, of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, presented the findings. “PROTEUS is the largest therapeutic trial in localized prostate cancer,” she said. “These are very high-risk patients.”

Mary-Ellen Taplin, MD, FASCO

“The results support the perioperative use of apalutamide plus ADT as a new standard of care for patients with localized high-risk prostate cancer,” she reported.

Patients treated with apalutamide plus ADT (ie, LHRH agonists, LHRH antagonists, androgen receptor blockers) were nine times more likely to have little to no cancer remaining in the prostate after surgery. They also had a 20% lower risk of metastasis or death. The treatment combination reduced the risk of an oncologic event or death by 29% and delayed subsequent local, regional, or systemic therapy by nearly 3 years; Dr. Taplin noted that patients treated with apalutamide plus ADT did not need subsequent therapy for a median of 5 years after completing study treatment.

Study Rationale and Design

Despite refinements in radical prostatectomy as a curative-intent therapy for patients with high-risk disease (ie, Grade Groups 3 to 5, with a majority having a Gleason score of 8 or higher), more than half of these patients will relapse, Dr. Taplin noted. Once metastases develop, the prognosis is poor, with a median time from metastasis to death of 3 to 5 years.

PROTEUS tested whether intensifying treatment with apalutamide plus ADT before and after surgery could improve pathologic response and long-term outcomes. Patients were randomly assigned 1:1 to receive apalutamide at 240 mg daily plus ADT or placebo plus ADT. Treatment was given for 6 months before radical prostatectomy and resumed after surgery for another 6 months, with a 2-week hold before surgery and a 4-week hold after surgery. Adjuvant or salvage radiotherapy after radical prostatectomy was allowed at the investigator’s discretion.

The trial enrolled 2,109 patients with newly diagnosed high-risk localized or locally advanced prostate cancer in 18 countries. The median age was 66 years. Baseline characteristics were well balanced between the two groups: more than 95% of patients had Gleason score 8 to 10 disease, approximately 40% had baseline prostate-specific antigen levels greater than 20 ng/mL, 35% had at least clinical T3 disease, and 12% had nodal disease on conventional imaging. Median follow-up was 61.7 months.

The study was also simultaneously published in The New England Journal of Medicine.²

Dual Primary Endpoints Met

The study’s dual primary endpoints were pathologic complete response or minimal residual disease (pCR/MRD), and metastasis-free survival, both assessed by blinded independent central review. pCR/MRD was defined as no residual tumor or minimal residual tumor of 5 mm or less in prostate-confined disease, without lymph node involvement.

The pathologic response endpoint favored apalutamide plus ADT. The pCR/MRD rate was 8.9% in the apalutamide group vs 1.0% in the placebo group, for an odds ratio of 10.17 (P < .0001). More than half of the responses in the apalutamide cohort were pathologic complete responses, Dr. Taplin reported.

An exploratory measure of residual cancer burden also favored apalutamide plus ADT: 30.6% vs 11.7% (P < .0001).

Metastasis-free survival by blinded independent central review was also significantly improved. The risk of metastasis or death was reduced by 20% with apalutamide plus ADT compared with placebo plus ADT (hazard ratio [HR] = 0.80; P = .0169). The 5-year metastasis-free survival rate was 78.2% with apalutamide plus ADT vs 73.5% with placebo plus ADT; median metastasis-free survival was not reached in either group.

Investigator-assessed metastasis-free survival, an exploratory endpoint that allowed investigators to incorporate clinical information such as prostate-specific antigen values, symptoms, and imaging, was consistent with the primary analysis (HR = 0.74; P = .0004).

Patients were randomized from July 15, 2019, to June 30, 2022. During the trial, PSMA-PET became the standard and preferred imaging modality for staging localized and relapsed prostate cancer, Dr. Taplin explained. PROTEUS was therefore amended to incorporate PSMA-PET as part of a composite metastasis-free survival endpoint; approximately 70% of patients underwent PSMA-PET imaging.

Secondary Endpoints Favored Apalutamide Plus ADT

The secondary endpoints showed that the gains seen at surgery translated into fewer and later clinical events. Median event-free survival was 57.1 months with apalutamide plus ADT vs 38.4 months with placebo plus ADT, corresponding to a 29% reduction in the risk of an oncologic event or death (HR = 0.71; P < .0001).

The delay in additional therapy was particularly notable. Median time to first subsequent local, regional, or systemic therapy, including reinitiation of ADT, was 74.2 months with apalutamide plus ADT vs 41.5 months with placebo plus ADT (HR = 0.65; P < .0001). Fewer patients in the apalutamide group went on to receive subsequent systemic therapy (26.7% vs 36.4%) or postoperative radiotherapy (13.0% vs 18.4%), extending the treatment-free interval after radical prostatectomy.

Apalutamide plus ADT also reduced the risk of distant metastasis by 32% (HR = 0.68; P = .0002). At 5 years, 82.8% of patients in the apalutamide group were free of distant metastasis compared with 76.2% in the placebo group.

Metastasis-free survival by conventional imaging alone was not statistically significant (HR = 0.84; P = .15). Dr. Taplin said this analysis lost power because of the small number of events, in large part because PSMA-PET evaluation and subsequent therapy delayed the development of metastasis detectable by conventional imaging.

No New Safety Signals Identified

The safety profile of apalutamide plus ADT was consistent with prior studies, Dr. Taplin reported. Grade 3 or 4 treatment-emergent adverse events occurred in 39.6% of patients treated with apalutamide plus ADT and 31.0% of those treated with placebo plus ADT. Discontinuation due to treatment-emergent adverse events occurred in 7.4% vs 2.7%, respectively.

Treatment-related grade 3 or 4 adverse events occurred in 27.5% of patients in the apalutamide group and 18.9% of those in the placebo group. Treatment-related adverse events leading to death occurred in 0.7% vs 0.1%, respectively.

After 1 year of enrollment, the protocol was amended to require cardiovascular risk assessment and cardiology assessment in higher-risk patients at screening and 1 month before prostatectomy. “Importantly, after this amendment, there were no further treatment-related deaths in either cohort, underscoring the importance of patient selection,” Dr. Taplin said.

Skin rash, a known adverse event with apalutamide, was more common with apalutamide plus ADT: 33.0% vs 15.3% for all-grade rash and 5.9% vs 0.3% for grade 3 or higher rash. Dr. Taplin said algorithms for management of apalutamide-related rash allow the vast majority of patients to continue treatment.

Next Steps

The PROTEUS data set may help answer several questions raised by the final PROTEUS analysis, including which patients are most likely to benefit from the regimen and whether pathologic response can guide postoperative treatment. Planned analyses will examine biomarkers of benefit and resistance, correlations between major pathologic response and metastasis-free survival, surgical outcomes, and patient-reported quality of life. A separate PROTEUS substudy, not presented at ASCO, is comparing prostatectomy alone with the PROTEUS regimen plus prostatectomy.

“We are excited for future analyses, including the substudy comparing PROTEUS to prostatectomy alone, extensive biomarker assessments, and correlation of major pathologic response with [metastasis-free survival],” Dr. Taplin said. 

DISCLOSURE: Dr. Taplin reported honoraria from Amgen, Astellas Pharma, AstraZeneca, AXIS Medical Education, Blue Earth Diagnostics, Carden Jennings, DAVA Pharmaceuticals, Flare Therapeutics, Geode Therapeutics, GlaxoSmithKline, Interpublic GIS, Janssen-Ortho, Laekna, MJH Healthcare Holdings, Novartis, Pfizer, Physicians’ Education Resource, Research to Practice, and UpToDate; consulting or advisory roles with Astellas Pharma, AstraZeneca, BioNTech, Blue Earth Diagnostics, Flare Therapeutics, Geode Therapeutics, GlaxoSmithKline, Janssen-Ortho, Laekna, Novartis, Pfizer, and UpToDate; institutional research funding from Janssen-Ortho; and travel, accommodations, or expenses from Advanced Prostate Cancer Society, Prostate Cancer Foundation, and Southwest Prostate Cancer Symposium.

REFERENCES

1. Taplin M-E, et al: Perioperative apalutamide plus androgen-deprivation therapy vs placebo plus ADT with radical prostatectomy in high-risk localized or locally advanced prostate cancer: Final analysis of the PROTEUS phase III study. 2026 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2026.

2. Taplin M-E, Gleave M, Shore ND, et al: Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. May 31, 2026.

EXPERT POINT OF VIEW

Formal discussant Declan G. Murphy, MB BCh, a urologist and Director of Genitourinary Oncology at Peter MacCallum Cancer Centre, Melbourne, Australia, emphasized the importance of the phase III PROTEUS trial findings presented by Mary-Ellen Taplin, MD, FASCO, during the Plenary Session at the 2026 ASCO Annual Meeting.¹ Dr. Taplin reported the final analysis of the study, which showed that adding apalutamide to androgen-deprivation therapy (ADT) before and after radical prostatectomy significantly improved both major pathologic response and metastasis-free survival in patients with high-risk localized or locally advanced prostate cancer.

Declan G. Murphy, MB BCh

Dr. Murphy emphasized that the PROTEUS results should be applied thoughtfully. “Not all high-risk prostate cancer is the same,” he said, noting that some good-prognosis patients with high-risk features do well with surgery alone, whereas poorer-risk patients often require a multimodal approach.

At the same time, he described PROTEUS as “a landmark trial” and “a very important moment” for the prostate cancer field. “My conclusion is that perioperative ADT and apalutamide will become a new standard of care,” he said.

ADT in the Control Arm

Dr. Murphy addressed one of the central design questions in PROTEUS: the use of ADT in the control arm. ADT is not routinely recommended as perioperative therapy before radical prostatectomy in many regions, he said, because prior evidence has not shown improvements in metastasis-free or overall survival, even though ADT may improve some pathologic outcomes. Still, he said he was not concerned about the control arm because ADT does not worsen outcomes and may have been used for blinding, regional practice, and regulatory reasons. The ongoing substudy comparing prostatectomy alone with the PROTEUS regimen will help clarify the effect of the full approach against surgery alone.

The pathologic findings may help guide future studies of treatment tailoring, Dr. Murphy said. Although pCR/MRD was ninefold higher with apalutamide plus ADT, the vast majority of patients still had residual disease after systemic therapy. “Systemic therapy alone is not enough,” he said. “Local control matters.” Residual cancer burden may eventually help determine whether all patients need the adjuvant portion of therapy, although that approach remains to be studied.

He also placed the metastasis-free survival endpoint in context. Metastasis-free survival is a recognized surrogate for overall survival in localized prostate cancer when assessed by conventional imaging, but it has not been validated as an overall survival surrogate when PSMA-PET/CT is incorporated into a composite endpoint, he said. Still, he welcomed the inclusion of PSMA-PET in PROTEUS, calling it “the now and the future of prostate cancer staging.”

William K. Oh, MD, of Yale School of Medicine and an ASCO Expert in genitourinary cancers, similarly characterized PROTEUS as “the first convincing randomized controlled trial demonstrating improvement in clinically meaningful endpoints in patients with high-risk localized prostate cancer treated with radical prostatectomy.” He also noted that the regimen has not yet been directly compared with upfront surgery alone or radiation therapy plus ADT.

William K. Oh, MD

During an ASCO press briefing ahead of the meeting, Dr. Oh called the study “paradigm shifting” and said prior systemic therapy approaches with surgery had reduced tumor burden in the prostate but had not produced meaningful long-term outcomes. In PROTEUS, he said, patients who received apalutamide plus ADT had significantly better outcomes on clinically meaningful endpoints. “This is a very important study,” Dr. Oh said. “I think it will change the standard of care for many of these patients who are candidates for surgery and have high-risk localized prostate cancer.”

Dr. Murphy also compared PROTEUS with systemic intensification trials in the radiotherapy setting, including the phase III ENZARAD study (ClinicalTrials.gov ID: NCT02446444), which sought to determine the effectiveness of enzalutamide as part of adjuvant ADT in men having radiation therapy for localized prostate cancer at high risk of recurrence.² PROTEUS and ENZARAD had similar baseline characteristics in several respects, he noted, yet ENZARAD was negative for metastasis-free survival whereas PROTEUS was positive. Whether the difference reflects the androgen receptor pathway inhibitor used, the imaging approach, or surgery itself remains an open question.

He said additional data will be important, including cancer-specific and overall survival, subgroup analyses to identify which patients benefit most, quality-of-life and surgical outcomes, and adverse events. He pointed out, however, that the reduction and delay in later treatment may be among the most patient-relevant findings from PROTEUS.

“For patients with high-risk prostate cancer, they are typically looking at a journey of 10 to 15 years,” he said. “Delaying, or perhaps avoiding altogether, requirements for additional treatments like this is profoundly meaningful.”

Dr. Murphy summarized the clinical implication simply: “All of this adds up to a much better patient journey.” 

DISCLOSURE: Dr. Murphy reported honoraria from Astellas Pharma, Bayer, Cipla, CIVCO, Clarity Pharmaceuticals, Intuitive, Ipsen, Johnson & Johnson/Janssen, Mundipharma, Novartis, and Pfizer; consulting or advisory roles with Astellas Pharma, AstraZeneca, Bayer, Bayer Schering Pharma, and Janssen Oncology; and travel, accommodations, or expenses from Device Technologies. Dr. Oh reported stock and other ownership interests in Archetype Therapeutics, GeneDx, NTx Bio, and Previvor Care; and consulting or advisory roles with Abbott Diagnostics, AstraZeneca, Cytogen, Novartis, Pfizer, and VieCure.

REFERENCES

1. Taplin M-E, Gleave M, Shore ND, et al: Perioperative (neoadjuvant and adjuvant) apalutamide plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy with radical prostatectomy in high-risk localized or locally advanced prostate cancer: Final analysis of the PROTEUS phase III study. 2026 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2026.2.

2. Nguyen PL, Sweeney C, Stockler MR, et al: Randomised phase III trial of androgen deprivation therapy (ADT) with radiation therapy with or without enzalutamide for high risk, clinically localised prostate cancer: ENZARAD (ANZUP 1303). Ann Oncol 36:S1628-S1629, 2025.