Neoadjuvant Apalutamide With or Without Abiraterone Acetate Plus Prednisone and Gonadotropin-Releasing Hormone Agonist Prior to Nerve-Sparing Radical Prostatectomy in High-Risk Prostate Cancer: Protocol for a Randomized Phase 2 Trial.

Abstract

Radical prostatectomy (RP) is an accepted, definitive treatment for appropriately selected men with high-risk localized prostate cancer (PCa). However, neoadjuvant androgen receptor inhibition prior to RP is not currently the standard of care. Wide resection of the neurovascular bundles may improve local oncologic control but can adversely affect postoperative erectile function and urinary continence. Apalutamide directly inhibits the androgen receptor, while abiraterone acetate inhibits cytochrome P450 17A1-mediated androgen synthesis and is often administered with prednisone. Gonadotropin-releasing hormone (GnRH) agonists further suppress testicular androgen production. Intensified androgen pathway inhibition prior to surgery may therefore downstage localized disease and facilitate bilateral nerve-sparing RP. This study was defined to evaluate whether 3 months of neoadjuvant apalutamide-based therapy before RP improves postoperative potency recovery by 12 months compared with immediate RP in men with high-risk localized PCa. Secondary objectives include evaluation of postoperative continence, pathological outcomes, biochemical recurrence, perioperative outcomes, and quality of life (QoL). This is a prospective, multicenter, randomized phase 2 clinical trial (ClinicalTrials.gov: NCT02949284). Eligible patients with high-risk PCa were randomized 1:1:1 to (1) apalutamide 240 mg daily for 3 months followed by RP, (2) apalutamide 240 mg daily with abiraterone acetate 1000 mg plus prednisone 10 mg daily and a GnRH agonist for 3 months followed by RP, or (3) immediate RP without neoadjuvant therapy. The primary end point is potency recovery by 12 months postoperatively, defined as the ability to penetrate in sexual intercourse in more than half of attempts. Secondary end points include continence recovery, pathological response, positive surgical margins, biochemical recurrence, perioperative outcomes, and QoL. The primary comparisons evaluate each experimental arm against the surgery-only arm. Pairwise comparisons of the primary end point will use 1-sided Fisher exact tests with a Bonferroni adjustment. Additional continuous and categorical outcomes will be analyzed using appropriate nonparametric or categorical tests, and biochemical recurrence-free survival will be assessed using Kaplan-Meier analysis. As of March 2026, patient enrollment has been completed. A total of 96 patients provided consent and were screened, 88 were randomized, and 73 received the assigned treatment and were included in the final analysis cohort. Study accrual began on June 20, 2017, and enrollment was completed in June 2024. The prespecified postoperative follow-up period extended beyond 24 months, with a study data cutoff date of June 30, 2025. Data collection for the primary and secondary outcomes has been completed, with final expected results anticipated in January 2027. This randomized phase 2 trial was designed to assess whether short-term androgen pathway inhibition can improve postoperative functional outcomes while maintaining oncologic outcomes in men undergoing nerve-sparing RP for high-risk localized PCa.