Perioperative apalutamide in high-risk localized or locally advanced prostate cancer: Is PROTEUS trial practice changing?

SUMMARY

Radical prostatectomy (RP) with pelvic lymph node dissection offers a potential cure in high-risk localized or locally advanced prostate cancer (HR-LPC/LAPC), yet up to half of treated men relapse within 5 years. Earlier attempts to add systemic therapy before or after surgery had not improved survival, leaving surgery alone as the mainstay.

PROTEUS (NCT03767244)[1] is the largest randomized trial of systemic therapy in localized prostate cancer. The rationale was that potent androgen-receptor blockade administered before and after surgery might eliminate occult micrometastatic disease and enhance local tumour clearance within the prostate. In this double-blind, phase 3 trial, 2109 men with HR-LPC/LAPC received androgen-deprivation therapy (ADT) plus apalutamide (240 mg/day) or ADT plus placebo, each for six 28-day cycles before and after RP. Co-primary endpoints were pathological complete response/minimal residual disease (pCR/MRD; ypT2 or lower with residual tumor ≤5 mm) and metastasis-free survival (MFS), assessed by conventional imaging or (PSMA-PET) Prostate-Specific Membrane Antigen Positron Emission Tomography.

At a median follow-up of 61.7 months, both endpoints favored apalutamide. pCR/MRD was almost ten-fold higher with apalutamide (8.9% vs. 1.0%; odds ratio, 10.17; P < 0.001), and 5-year MFS was 78.2% vs. 73.5% (hazard ratio, 0.80; P = 0.02). Event-free survival, time to first subsequent treatment, and time to distant metastasis all favored apalutamide (P < 0.001 for all).

Grade 3 or 4 adverse events were more common with apalutamide (39.6% vs. 31.0%), mainly rash. Testosterone recovery was similar between groups and surgical feasibility was preserved.

COMMENTS

PROTEUS is the first phase 3 trial in which perioperative systemic intensification improved a clinically meaningful outcome after RP in high-risk disease.[1] Such benefit had been elusive in the CALGB 90203 trial (n = 788), where neoadjuvant docetaxel plus ADT did not meet its primary endpoint of 3-year biochemical progression-free survival, although secondary analyses suggested benefit in MFS and overall survival.[2] The near ten-fold rise in pCR/MRD is an early, biologically plausible signal, consistent with the MFS benefit and with the broader low-residual cancer-burden endpoint (30.6% vs. 11.7%). However, the absolute pathological response rate remained modest, with only 8.9% of patients achieving pCR/MRD. These findings should therefore be interpreted with caution until they translate into durable survival benefits.

The trial also builds on a decade of smaller, hypothesis-generating studies. In the randomized phase 2 ARNEO trial, a higher proportion of men achieved minimal residual disease with neoadjuvant degarelix plus apalutamide than with degarelix alone (38% vs. 9.1%; relative risk, 4.2; 95% confidence interval [CI], 1.5 to 11; P = 0.002), although the trial was not powered for survival.[3] In the single-arm apalutamide following RP study (n = 108), adjuvant apalutamide plus ADT for 12 cycles (28 days each) produced a 24-month biochemical recurrence-free rate of 100% (90% CI, 93 to 100), with testosterone recovery (≥150 ng/dL) in 77% of men, 12 months after treatment completion.[4] By contrast, the single-arm neoadjuvant apalutamide and RP trial (n = 30) achieved no pCR with neoadjuvant apalutamide alone (median reduction in cancer burden: 41.7%), indicating that androgen receptor pathway inhibition without an ADT backbone is inadequate.[5] PROTEUS provides the adequately powered, blinded, randomized confirmation that these studies lacked.

Several points warrant caution. MFS by conventional imaging did not reach statistical significance (hazard ratio: 0.84), although the directionally consistent estimate does not exclude a treatment effect. Increasing PSMA-PET use may have reduced power through earlier metastasis detection and stage migration analogous to the Will Rogers phenomenon. Overall survival remains immature (hazard ratio for death, 1.08, within the prespecified nondetrimental threshold but far from confirmatory), and follow-up was too short to confirm a survival benefit, so it remains unclear whether earlier treatment improves OS or merely advances toxicity. Mortality was nearly double in men aged 75 years or older (15.2% vs. 8.0%), reinforcing the need for careful patient selection.

Urinary incontinence and erectile dysfunction were similar between arms, and positive surgical margins were lower with apalutamide (20.9% vs. 42.7%); however, granular data on nerve-sparing, continence recovery, and validated potency outcomes were not reported.

Most importantly, PROTEUS compared ADT plus apalutamide with ADT plus placebo, not with standard surgery with salvage therapy if needed; a substudy is underway. Even in the apalutamide arm, 42.4% still required subsequent therapy, showing the benefit is partial rather than curative for many. Until that comparison and validated biomarkers (Gleason grade group 4-5, cT3-4/node-positive disease, genomic classifiers, and ctDNA-based MRD testing) identify who truly benefits, uniform adoption risks a year of chemical castration and Grade 3/4 adverse events (39.6% vs. 31.0%) in men who might have been cured by surgery alone.

On balance, perioperative apalutamide plus ADT represents a promising investigational strategy for carefully selected men with HR-LPC/LAPC; however, its role in clinical practice awaits comparison with contemporary standard-of-care surgery, mature survival data, and clearer evidence regarding functional outcomes.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.