Final Results of the Randomised Phase 2 Trial of Neoadjuvant Degarelix with or Without Apalutamide Prior to Radical Prostatectomy for High-risk Prostate Cancer (ARNEO).

[BACKGROUND AND OBJECTIVE] High-risk prostate cancer (PCa) carries a substantial risk of recurrence and progression after radical prostatectomy (RP). The ARNEO trial previously showed that apalutamide (APA) plus degarelix (DEG) improved the rates of minimal residual disease (MRD) and organ-confined pathology (ypT2) compared with matching placebo (PBO). This study aims to assess the oncological and quality-of-life outcomes of neoadjuvant DEG + APA compared with DEG + PBO.

[METHODS] ARNEO was a double-blind, randomised, PBO-controlled phase 2 trial investigating neoadjuvant DEG + APA in high-risk PCa patients eligible for RP. Patients received 3 mo of neoadjuvant DEG + APA or DEG + PBO. No adjuvant or salvage therapy was given unless biochemical recurrence (BCR) occurred. Quality-of-life data were collected at predefined time points. The prespecified secondary endpoints included a between-arm comparison of testosterone recovery (testosterone ≥150 ng/ml), BCR within 3 yr (prostate-specific antigen ≥0.2 ng/ml), BCR-free survival (BCR-FS), and quality of life according to treatment allocation. Quality of life was assessed using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form, International Index of Erectile Function-5 items, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaires. Exploratory analyses included metastasis-free survival (MFS) and the relation of outcomes according to pathological outcomes.

[KEY FINDINGS AND LIMITATIONS] With a median follow-up of 54 mo, the 3-yr BCR rate was not significantly different between groups (24% with DEG + APA vs 39% with DEG + PBO; relative risk 0.63 [95% confidence interval {CI} 0.34-1.19], p = 0.18). BCR-FS was not associated with treatment allocation (hazard ratio 0.72 [95% CI 0.37-1.41]; p = 0.34) or MRD achieved (p = 0.93). However, BCR-FS was significantly longer in patients with ypT2 or specimen-confined disease (p ≤ 0.0001). Similar outcomes regarding 3-yr BCR rates and MFS were found. The median testosterone (>150 ng/dl) recovery time was 5 mo in both the groups (p = 0.36). Quality-of-life outcomes were not different at each time point (p > 0.47). Importantly, the ARNEO trial was powered for a difference in MRD rates (primary endpoint) and not for the reported secondary endpoints.

[CONCLUSIONS AND CLINICAL IMPLICATIONS] At 3-yr follow-up, no differences were seen in the 3-yr BCR rate or BCR-FS between patients treated with neoadjuvant DEG + APA and those treated with DEG + PBO. Achieving MRD was not predictive of better outcomes, whereas ypT2 and specimen-confined disease were strongly associated with improved BCR-FS and MFS. Quality of life remained similar between groups at all time points.