For patients with high-risk localized or locally advanced prostate cancer (HR-LPC/LAPC), radical prostatectomy (RP) is potentially curative, yet roughly half of these patients ultimately relapse. The final analysis of the phase 3 PROTEUS trial, presented as a plenary late-breaking abstract¹ at the 2026 ASCO Annual Meeting, suggests that adding 1 year of perioperative apalutamide to androgen deprivation therapy (ADT) around surgery may change that calculus, and may represent a new standard of care for this population.

PROTEUS was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 2109 patients with newly diagnosed HR-LPC/LAPC across 184 sites in 18 countries. Patients were randomized 1:1 to apalutamide (240 mg/day) plus ADT or placebo plus ADT for 6 months as neoadjuvant therapy, followed by RP with pelvic lymph node dissection, and then 6 more months of the same assigned therapy as adjuvant treatment. Baseline characteristics were well balanced between arms: median age was 66 years, and roughly 96% of patients had Gleason scores of ≥8. Median follow-up at the February 2026 data cutoff was 61.7 months.

The trial’s dual primary end points, assessed by blinded independent central review, were both met. Pathologic complete response or minimal residual disease, defined as ≤ypT2 with tumor ≤5 mm) occurred in 8.9% of patients on apalutamide versus 1.0% on placebo, an approximately 9-fold improvement (odds ratio [OR], 10.17; 95% CI, 5.27-19.64; P<.0001). Metastasis-free survival (MFS) was also significantly improved, with a 5-year rate of 78.2% versus 73.5% (hazard ratio [HR], 0.80; 95% CI, 0.67-0.96; P=.0169), corresponding to a 20% reduction in the risk of metastasis or death. Investigator-assessed MFS showed a similar benefit (HR, 0.74; 95% CI, 0.62-0.87).

Secondary end points, tested hierarchically, consistently favored the apalutamide arm. Event-free survival nearly doubled, with a median of 57.1 months versus 38.4 months (HR, 0.71; 95% CI, 0.63-0.80). Time to first subsequent therapy was extended by nearly 3 years (74.2 vs 41.5 months; HR, 0.65; 95% CI, 0.57-0.73), and time to distant metastasis was reduced by 32% (HR, 0.68; 95% CI, 0.55-0.83), with 5-year distant metastasis-free rates of 82.8% versus 76.2%. An exploratory measure of residual cancer burden corroborated the primary pathologic findings (30.6% vs 11.7%; OR, 3.36).

These gains came with a manageable but real increase in toxicity. Grade 3/4 treatment-related adverse events occurred in 27.5% of apalutamide-treated patients versus 18.9% on placebo, with discontinuation due to adverse events in 7.4% versus 2.7%. Skin rash was the most common adverse event of clinical interest, affecting 33.0% of patients on apalutamide (any grade) versus 15.3% on placebo, though most cases were manageable with dose modification. Testosterone recovery after treatment was slightly slower in the apalutamide arm (median 8.1 vs 6.6 months to recovery ≥200 ng/dL), though the majority of patients in both arms ultimately recovered.

For community oncologists and urologists, several practical points stand out. Apalutamide and placebo were held 2 weeks before RP and resumed 4 weeks after surgery, a perioperative window that will require close coordination between medical oncology and urology. Patients should be counseled up front about the 1-year treatment duration and the higher likelihood of dose interruptions for rash, which was the dominant driver of dose modification. Given the magnitude of benefit across both pathologic and time-to-event end points, and with results reported alongside a simultaneous full publication in the New England Journal of Medicine,² PROTEUS is likely to prompt discussion about incorporating perioperative androgen receptor pathway inhibition into multidisciplinary treatment planning for high-risk, surgically eligible prostate cancer patients.

References

1. Taplin ME, Gleave M, Shore ND, et al. 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. J Clin Oncol. 2026;44(suppl 17). Abstract LBA1. doi:10.1200/JCO.2026.44.17_suppl.LBA1
2. Taplin ME, Gleave M, Shore ND, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. 2026;395:546-560. DOI: 10.1056/NEJMoa2603878