Perioperative Apalutamide Plus ADT Reduces Risk of Metastasis or Death in High-Risk Localized Prostate Cancer

Perioperative apalutamide (Erleada) plus androgen deprivation therapy (ADT) significantly reduced the risk of metastasis or death and made patients with high-risk localized or locally advanced prostate cancer nine times more likely to have little to no cancer remaining in the prostate after surgery compared with placebo plus ADT, according to findings from the phase 3 PROTEUS trial presented at the 2026 ASCO Annual Meeting.^1,2

The pathological complete response or minimal residual disease (pCR/MRD) rate per blinded independent central review (BICR) was 8.9% (94 of 1057 patients) in the apalutamide plus ADT arm versus 1.0% (10 of 1052 patients) in the placebo plus ADT arm (odds ratio, 10.17; P < .0001), meaning patients receiving apalutamide were approximately nine times more likely to have little to no cancer remaining at the time of radical prostatectomy.

Metastasis-free survival (MFS), which was assessed by BICR across the full perioperative treatment period, was also significantly improved with apalutamide plus ADT. At 5 years, an estimated 78.2% of patients in the apalutamide arm remained metastasis free and alive compared with 73.5% in the placebo arm (HR, 0.80; 95% CI, 0.67-0.96; p = 0.02), representing a 20% reduction in the risk of metastasis or death.

The median EFS was 57.1 months with apalutamide plus ADT versus 38.4 months with placebo plus ADT, a difference of approximately 1.6 years (HR, 0.71; 95% CI, 0.63-0.80; P < .0001), representing a 29% reduction in the risk of an EFS event.

The time to first subsequent local or systemic therapy was also significantly prolonged. Median time to subsequent therapy was 74.2 months with apalutamide plus ADT versus 41.5 months with placebo plus ADT (HR, 0.65; 95% CI, 0.57-0.73; P < .0001). This translates to a 5-year treatment-free interval after completing 1 year of perioperative apalutamide plus ADT, and nearly 3 additional years free of subsequent therapy compared with placebo plus ADT.

“These results support the perioperative use of apalutamide plus ADT as a new standard of care for patients with localized high risk prostate cancer,” said said lead study author Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute.

Safety

The safety profile of apalutamide plus ADT was consistent with its established profile from prior studies. Treatment-emergent adverse events (TEAEs) of special interest occurred in 37.9% of patients in the apalutamide arm (grade ≥3: 8.6%) versus 20.4% in the placebo arm (grade ≥3: 2.2%). The most common TEAE of special interest was skin rash, reported in 33.0% of apalutamide patients (grade ≥3: 5.9%) versus 15.3% of placebo patients (grade ≥3: 0.3%). Fatigue was similarly common between arms (27.7% with apalutamide versus 26.8% with placebo) with low rates of grade ≥3 fatigue in both arms (0.4% vs 0.1%).

Other TEAEs of special interest occurring at low rates in both arms included 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%). Any treatment-related adverse event occurred in 95.2% (grade ≥3: 27.5%) of apalutamide patients versus 93.8% (grade ≥3: 18.9%) of placebo patients. Treatment-related adverse events leading to death occurred in 7 patients (0.7%) in the apalutamide arm and 1 patient (0.1%) in the placebo arm.

Study Design and Context

PROTEUS is a phase 3, randomized, double-blind, placebo-controlled study that enrolled 2109 patients from 184 sites across 18 countries and regions. Patients were randomized 1:1 from July 15, 2019, to June 30, 2022, to receive either apalutamide plus ADT or placebo plus ADT perioperatively in combination with radical prostatectomy.

The dual primary end points were pCR/MRD assessed by BICR before surgery and MFS by conventional imaging (CT, MRI, or bone scan), PSMA-PET imaging, or histopathology. Key secondary endpoints included EFS, time to first subsequent local or systemic treatment, time to distant metastasis, and no evidence of disease at 4 years. A substudy is ongoing to further evaluate the role of apalutamide plus ADT plus radical prostatectomy versus radical prostatectomy alone.

Expert Perspective

Following Taplin’s presentation of the results at ASCO, William K. Oh, MD, Yale School of Medicine and an ASCO Expert in genitourinary cancers, shared his expert interpretation of the PROTEUS findings:

“This is a very important study in that what we have seen, as Dr Taplin pointed out, for decades is that trying to combine systemic therapy with surgery, and in general, systemic therapy, has never made surgery for high-risk localized prostate cancer better. It has sometimes reduced the burden of disease in the prostate, but it has never had a meaningful long-term outcome. So in this trial, ADT for a year perioperatively 6 months before and 6 months after was the control arm, and the results show that in the experimental arm of patients who also received apalutamide with ADT, there were significantly better outcomes with what I would argue are clinically meaningful endpoints of pCR/MRD and MFS. And MFS, specifically, has been shown to be a validated surrogate for overall survival.

“So, what we're seeing here is, again, an early signal that these patients are likely to have a better long-term outcome, but there are unanswered questions. For example, there's no comparison to a standard of care, which is ADT plus radiation therapy for these patients, which is a very commonly used standard of care, and there's no comparison to surgery alone followed by adjuvant therapy. We're going to need more data on those categories to understand who the best patients are for this type of approach. That being said, this really is a very, very important study that I think will change the standard of care for many of these patients who are candidates for surgery and have high-risk localized prostate cancer.”

References

1. Taplin ME, Gleave M, Shore ND, et al. Perioperative (neoadjuvant and adjuvant) apalutamide + ADT vs placebo + ADT with radical prostatectomy in high-risk localized or locally advanced prostate cancer: final analysis of the PROTEUS phase 3 study. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1)

2. American Society of Clinical Oncology. Potential new targeted treatment option for people with localized high-risk prostate cancer. ASCO Press Center. Published May 31, 2026. Accessed May 31, 2026. https://www.asco.org/about-asco/press-center/potential-new-targeted-treatment-localized-high-risk-prostate