Perioperative apalutamide cuts metastasis and death risk in high-risk prostate cancer substudy

An international phase 3 substudy presented at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid and published in European Urology reports that adding the next-generation androgen-receptor pathway inhibitor (ARPI) apalutamide to hormone therapy before and after prostate cancer surgery improved outcomes for men with high-risk localized or locally advanced prostate cancer compared with radical prostatectomy alone. The analysis, co-led by principal investigator Mary-Ellen Taplin, MD, a medical oncologist at Dana-Farber Cancer Institute, and presented by Alberto Briganti, MD, PhD, Professor of Urology at Vita-Salute San Raffaele University in Milan, was designed to answer a question left open by the main PROTEUS trial: how the perioperative regimen performs against standard-of-care prostatectomy rather than against hormone therapy by itself.

The PROTEUS substudy randomized 408 patients with newly diagnosed high-risk localized or locally advanced prostate cancer in a 1:3 design to either perioperative apalutamide plus androgen-deprivation hormone therapy (ADT) or standard-of-care radical prostatectomy. Patients in the experimental arm received apalutamide plus ADT for six months before and after radical prostatectomy with pelvic lymph-node dissection, while the control group underwent prostatectomy alone. The primary endpoint was event-free survival, with events defined as PSA relapse, clinical relapse, or relapse detected on PSMA-PET or conventional imaging. Apalutamide is already approved for metastatic castration-sensitive prostate cancer and for nonmetastatic castration-resistant prostate cancer.

After a median follow-up of 37.8 months, the combination of apalutamide, ADT and prostatectomy produced a 62 percent improvement in event-free survival and a 51 percent reduction in the risk of metastasis or death compared with surgery alone. The perioperative regimen also reduced the risk of starting a subsequent therapy by 71 percent, and 50 percent fewer patients in the combination arm had begun subsequent therapy by three years. The investigators reported that side effects were consistent with data from previously reported studies of the regimen.

“Following the presentation of the PROTEUS results at ASCO, an important question remained: how does this regimen compare with standard of care prostatectomy? Addressing that question is essential to understanding the full clinical significance of these findings and determining how they can best inform treatment decisions for patients with high-risk localized prostate cancer,” said Taplin. “This substudy demonstrated superior efficacy of perioperative apalutamide plus ADT over radical prostatectomy alone in high-risk localized/locally advanced prostate cancer, reinforcing the PROTEUS main study findings.”

The substudy builds on earlier Dana-Farber research led by Taplin, presented earlier in 2026 at the American Society for Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine, which compared apalutamide plus ADT with ADT alone around surgery. In that main analysis, patients treated with the apalutamide plus hormone therapy regimen were nine times more likely to have little to no cancer present at surgery, experienced a 20 percent reduction in the risk of metastases or death, and delayed the start of subsequent therapy by 33 months compared with ADT alone. The new substudy extends those results by benchmarking the perioperative approach directly against radical prostatectomy without additional systemic therapy.

The event-free survival endpoint used in the substudy captures a broad spectrum of treatment failure, ranging from biochemical PSA relapse to relapse detected on PSMA-PET or conventional imaging. Because events were counted across these modalities, the endpoint reflects both biochemical and clinically or radiographically detectable recurrence in the studied population.

“Combined evidence from the main and substudy support perioperative apalutamide plus ADT and prostatectomy as a potential treatment of choice in patients fit for surgery and systemic therapy,” said Taplin.

The trial was funded by Johnson & Johnson. As with any randomized substudy, the results reflect a median follow-up of 37.8 months in a defined population of 408 patients with newly diagnosed high-risk localized or locally advanced prostate cancer who were fit for surgery and systemic therapy. The data were published in European Urology on October 24, 2026, under the title “Radical Prostatectomy Alone in Patients with High-risk Localized or Locally Advanced Prostate Cancer from the PROTEUS Substudy.”

Subject of Research: Perioperative apalutamide plus androgen-deprivation therapy around radical prostatectomy in high-risk localized and locally advanced prostate cancer

Article Title: Perioperative apalutamide in high-risk localized or locally advanced prostate cancer substudy supports reduced risk of metastasis and death

Article References: Perioperative apalutamide in high-risk localized or locally advanced prostate cancer substudy supports reduced risk of metastasis and death. Original publication (Bibliographic details unavailable.)

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Keywords: prostate cancer, apalutamide, PROTEUS trial, radical prostatectomy, androgen-deprivation therapy, androgen-receptor pathway inhibitor, event-free survival, metastasis risk, Dana-Farber Cancer Institute, ESMO Congress 2026, European Urology, perioperative therapy