ASCO 2026: Perioperative apalutamide improves outcomes in high-risk localized prostate cancer

Clinical Takeaway: For patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy, adding apalutamide to androgen-deprivation therapy before and after surgery improved metastasis-free survival and other oncologic outcomes. These findings support treatment intensification in patients at high risk for recurrence, although increased toxicity, particularly rash, should be considered.

Despite curative-intent surgery, up to half of patients with high-risk localized or locally advanced prostate cancer experience recurrence within five years. Investigators in the phase 3 PROTEUS trial evaluated whether intensifying perioperative systemic therapy could improve long-term outcomes in this population.

The double-blind study randomized 2,109 patients with newly diagnosed high-risk localized or locally advanced prostate cancer to receive androgen-deprivation therapy (ADT) plus apalutamide or ADT plus placebo for six cycles before radical prostatectomy and for six cycles after surgery. Median follow-up was 61.7 months.

Patients receiving apalutamide were significantly more likely to achieve a pathologic complete response or minimal residual disease at surgery, occurring in 8.9% of patients compared with 1.0% in the placebo group (odds ratio, 10.17; P<0.001).

The trial also met its second primary endpoint. Five-year metastasis-free survival was 78.2% with apalutamide plus ADT versus 73.5% with ADT alone, representing a 20% reduction in the risk of distant metastasis or death (hazard ratio, 0.80; 95% confidence interval, 0.67-0.96; P=0.02).

Additional secondary endpoints also favored the intensified regimen, including event-free survival, time to first subsequent treatment, and time to distant metastasis.

Treatment-related toxicity was higher with apalutamide. Grade 3 or 4 adverse events occurred in 39.6% of patients receiving apalutamide compared with 31.0% of those receiving placebo, with the difference driven primarily by a higher incidence of rash.

The findings suggest that perioperative androgen receptor pathway inhibition may help reduce the risk of metastatic progression in patients with high-risk localized disease undergoing surgery, potentially extending the role of systemic treatment beyond the metastatic setting.

Source: Taplin ME, et al; PROTEUS Investigators. 2026, May 31. New Eng J Med. Perioperative apalutamide in high-risk localized prostate cancer