PROTEUS Substudy: Perioperative apalutamide plus ADT improves EFS vs surgery alone

The PROTEUS substudy demonstrated that adding 1 year of perioperative apalutamide (Erleada; APA) plus androgen deprivation therapy (ADT) to radical prostatectomy (RP) with pelvic lymph node dissection (PLND) reduced the risk of an event or death by 62% compared with RP plus PLND alone in patients with high-risk localized or locally advanced prostate cancer.¹

The data were presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.

The substudy fills a gap left by the phase 3 PROTEUS main study. That trial compared apalutamide plus ADT with placebo plus ADT and had no surgery-alone control arm.² The new comparison is against the care many surgical patients actually receive in clinical practice. In that control arm, the median event-free survival (EFS) was 19.1 months.

“The median 19.1 months EFS with standard of care highlights the high unmet need in this patient population,” said presenting author Alberto Briganti, MD, PhD, professor of urology at Vita-Salute San Raffaele University in Milan, Italy.

Trial design

PROTEUS substudy investigators randomly assigned 408 patients 1:3 to receive apalutamide 240 mg daily plus ADT (n = 102) or to RP plus PLND alone (n = 306). Patients in the apalutamide arm received 6 cycles of treatment before surgery and 6 cycles after. Patients in the control arm received no neoadjuvant therapy, and adjuvant treatment was left to physician discretion and local practice. Inclusion and exclusion criteria matched those of the main study (NCT03767244). Randomization took place between July 2022 and October 2023 at 83 sites in 15 countries and regions.

The 2 arms had similar baseline characteristics. Median age was 66 years in both arms, and more than 96% of patients had a Gleason score of 8 or higher. Roughly 30% had clinical T3 disease or higher, and about 7% had clinically node-positive disease on conventional imaging. Median follow-up was 37.8 months at the July 2026 data cutoff.

The primary end point was event-free survival (EFS). An event was defined as the first biochemical failure, local or regional recurrence (LRR), distant metastasis (DM), or death from any cause. LRR and DM were assessed by blinded independent central review using prostate-specific membrane antigen (PSMA)-PET or conventional imaging.

Efficacy

Median EFS was not reached in the apalutamide arm, compared with 19.1 months with surgery alone (HR, 0.38; 95% CI, 0.26 to 0.55; P < .0001). At 36 months, 63.0% (95% CI, 52.2 to 71.9) of patients in the apalutamide arm were event free, compared with 41.4% (95% CI, 35.6 to 47.1) in the control arm.

Investigators also ran landmark analyses to test whether the benefit lasted after testosterone recovered. Testosterone returned to 200 ng/dL or higher at a median of 20.7 months with APA + ADT, about 9 months after treatment ended. The EFS rate difference was 42 percentage points at 20 months, 37 points at 24 months, and 22 points at 36 months (all nominal P < .001).

Biochemical failure was the most common first event in both arms, occurring in 27 patients in the apalutamide arm and 92 patients in the surgery alone arm. LRR was a first event in 4 patients in the apalutamide arm and 51 in the control arm. DM was a first event in 4 and 28 patients, respectively.

Metastasis-free survival (MFS) by conventional or PSMA-PET imaging was a secondary end point. Apalutamide plus ADT was associated with a 51% lower risk of metastasis or death (HR, 0.49; 95% CI, 0.26 to 0.90; nominal P = .0193), and investigator-assessed MFS gave a consistent result (HR, 0.38; 95% CI, 0.22 to 0.66; P = .0004).

Time to first subsequent therapy was an exploratory end point. The median time to first subsequent therapy was 46 months in the apalutamide arm vs 12.3 months in the surgery alone arm, representing a 71% lower risk of starting subsequent therapy (HR, 0.29; 95% CI, 0.20 to 0.43; nominal P < .0001).

Briganti noted during the presentation that approximately 50% fewer patients started subsequent therapy by 3 years. At 36 months, 64.6% of patients in the apalutamide arm and 32% of patients in the surgery alone arm were free from subsequent therapy. Salvage radiotherapy, with or without ADT, was used in 16% vs 28% of patients, respectively.

Safety

Treatment-related adverse events (AEs) attributed to apalutamide plus ADT occurred in 76.2% of patients; 10.9% were grade 3 or 4. Investigators reported that surgery-related AEs were no more common with the addition of apalutamide plus ADT. These AEs occurred in 82.2% of the apalutamide arm vs 92.7% of the control arm, and no deaths were related to treatment.

Hot flush was the most common treatment-emergent AE with apalutamide (64% vs 0.7%). Rash occurred in 16% vs 0.7% and fatigue in 22% vs 2.8% of patients, respectively. Urinary incontinence (63% vs 66%) and erectile dysfunction (56% vs 62%) occurred at similar rates in the 2 arms. Grade 3 or higher treatment-emergent AEs occurred in 31% vs 22% of patients.

“Together with the PROTEUS main study, the PROTEUS substudy supports 1-year perioperative APA + ADT as a treatment option in patients with high-risk, localized, or local advanced prostate cancer who choose surgery and are fit for both surgery and systemic treatment,” Briganti concluded. “Perioperative APA plus ADT improves disease control and gives patients a longer time before starting subsequent therapy, with a 62% lower risk of recurrence or death, 51% lower risk of death or developing metastasis over time, approximately 50% fewer patients starting subsequent therapy, and at three times higher longer time to first subsequent therapy.”

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REFERENCES

1. Briganti A, Steuber T, Shore ND, et al. Perioperative apalutamide (APA) plus androgen-deprivation therapy (ADT) with radical prostatectomy plus pelvic lymph node dissection (RP + PLND) vs RP + PLND alone in patients (pts) 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. LBA53

2. 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