Apalutamide/ADT Improves EFS vs Surgery Alone in High-Risk Prostate Cancer

At the 2026 European Society for Medical Oncology (ESMO) Congress, Alberto Briganti, MD, PhD, Alberto Briganti, MD, PhD, full professor of urology at Vita-Salute San Raffaele University in Milan, presented results from the PROTEUS substudy (NCT03767244). In patients with high-risk localized or locally advanced prostate cancer, adding perioperative apalutamide (Erleada) and androgen deprivation therapy (ADT) to radical prostatectomy with pelvic lymph node dissection significantly improved event-free survival (EFS) compared with surgery alone.¹

The main phase 3 PROTEUS study data had already shown superior efficacy for 1 year of perioperative apalutamide plus ADT compared with an active comparator, but it did not include a surgery-alone control arm.² The substudy was designed to fill that gap by comparing the regimen with standard-of-care surgery.

After a median follow-up of 37.8 months, the substudy met its primary end point of EFS. Perioperative apalutamide plus ADT reduced the risk of an oncologic event or death by 62% (HR, 0.38; 95% CI, 0.26-0.55; P <.0001). Moreover, the median EFS was not reached with apalutamide plus ADT and was 19.1 months with surgery alone. At 36 months, the EFS rates were 63.0% (95% CI, 52.2%-71.9%) and 41.4% (95% CI, 35.6%-47.1%), respectively.

The benefit held over time, including after testosterone recovered. The median time to testosterone recovery of at least 200 ng/dL was 20.7 months, or about 9 months after the end of treatment. The EFS rates with apalutamide plus ADT vs surgery alone were:

• 20 months: 91% (95% CI, 85%-97%) vs 49% (95% CI, 43%-55%)
• 24 months: 84% (95% CI, 75%-90%) vs 46% (95% CI, 40%-52%)
• 36 months: 63% (95% CI, 52%-72%) vs 41% (95% CI, 36%-47%)

A first event occurred in 34.3% (n = 35/102) of patients in the apalutamide arm and 56.2% (n = 172/306) of those in the surgery-alone arm. Local or regional recurrences detected by imaging occurred in 4 patients vs 51 patients, and distant metastases in 4 vs 28 patients, respectively.

For the secondary end point of metastasis-free survival assessed by blinded independent central review (BICR), apalutamide plus ADT reduced the risk of metastasis or death by 51% (HR, 0.49; 95% CI, 0.26-0.90; nominal P = .0193). By local investigator assessment, the HR was 0.38 (95% CI, 0.22-0.66; nominal P = .0004).

In an exploratory analysis, the median time to first subsequent therapy was 46.0 months with apalutamide plus ADT vs 12.3 months with surgery alone (HR, 0.29; 95% CI, 0.20-0.43; nominal P <.0001). At 3 years, 64.6% (95% CI, 54.1%-73.3%) vs 32.0% (95% CI, 26.7%-37.5%) of patients had not started subsequent therapy. Salvage radiotherapy, with or without ADT, was used in 16% of the apalutamide arm vs 28% of the surgery-alone arm.

The open-label substudy randomly assigned 408 patients 1:3 to perioperative apalutamide plus ADT (n = 102) or radical prostatectomy with pelvic lymph node dissection alone (n = 306). Patients were enrolled across 83 sites in 15 countries or regions between July 27, 2022, and October 16, 2023.

Patients in the experimental arm received apalutamide 240 mg once daily plus ADT for 6 cycles before surgery and 6 cycles after. In the control arm, any adjuvant treatment after surgery followed local standard institutional practice and physician discretion. Randomization was stratified by nodal status (cN0 vs cN1), Gleason score (7 vs 8-10), and region.

EFS was defined as the time to the first of the following:

• biochemical failure, meaning PSA progression;
• local or regional recurrence;
• distant metastasis, assessed by BICR on PSMA PET or conventional imaging, or by histopathology;
• death from any cause.

Baseline characteristics were well balanced. The median age was 66 years in both arms, and more than 96% of patients in each arm had a Gleason score of 8 or higher.

Grade 3 or 4 treatment-related adverse events (AEs) attributed to apalutamide plus ADT occurred in 10.9% of patients. Grade 3 or 4 AEs related to surgery occurred in 16.8% of the apalutamide arm and 14.7% of the surgery-alone arm, and no treatment-related deaths occurred in either arm. The most common AE linked to apalutamide plus ADT was hot flashes, which occurred in 64% of patients in that arm vs 0.7% of those who had surgery alone. Rates of urinary incontinence (63% vs 66%) and erectile dysfunction (56% vs 62%) were similar between arms.

The investigators noted several limitations:

• The substudy used an open-label design.
• PSMA PET was not performed at screening.
• Follow-up was not long enough to assess overall survival.
• Enrollment was not enriched using biomarker profiling.

Briganti and colleagues concluded that, together with the main PROTEUS study, the substudy supports 1-year perioperative apalutamide plus ADT as a treatment option for patients with high-risk localized or locally advanced prostate cancer who are fit for surgery and systemic therapy.

References

1. Briganti A, Steuber T, Shore ND, et al. Perioperative apalutamide plus androgen deprivation therapy with radical prostatectomy plus pelvic lymph node dissection (RP + PLND) vs RP + PLND alone in patients with high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): PROTEUS substudy. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA53.
2. Taplin ME, Gleave M, Shore ND, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. 2026;395(6):546-560. doi:10.1056/NEJMoa2603878