Background: Enzalutamide (ENZA) + androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression and increased overall survival in men with mHSPC, regardless of baseline PSA levels (ARCHES; NCT02677896). This post hoc analysis investigated concordance between PSA progression and radiographic progression in patients with mHSPC. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. The concordance between radiographic progression and PSA progression, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, and between any rise in PSA above nadir was assessed. Results: In total, 267/1150 patients in ARCHES had radiographic progression (ENZA + ADT, n=79; PBO + ADT, n=188). At radiographic progression, the median (range) PSA for ENZA + ADT-treated patients was 2.25 ng/mL (0–1062.3 ng/mL) and 17.47 ng/mL (0–1779.5 ng/mL) for PBO + ADT-treated patients. Most patients (67%) treated with ENZA + ADT did not have PCWG2-defined PSA progression at radiographic progression, compared with 57% of those treated with PBO + ADT (Table). The median absolute and percentage rise in PSA from nadir to radiographic progression was 0.77 ng/mL and 200%, respectively, with ENZA + ADT compared with 12.23 ng/mL and 367%, respectively, with PBO + ADT. Conclusions: In this post hoc analysis of ARCHES, we found frequent discordance between radiographic progression and PSA progression by PCWG2 criteria or any PSA rise over nadir in patients with mHSPC treated with ENZA + ADT. Thus, regular imaging is recommended to detect radiographic progression among patients treated with potent androgen receptor pathway inhibitors, such as ENZA + ADT, as serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients. Clinical trial information: NCT02677896.

^aPSA progression is defined as a ≥25% increase and an absolute increase of ≥2 ng/mL above the nadir, confirmed by a second consecutive value at least 3 weeks later; ^bRadiographic progression was assessed by independent central review or death (defined as death from any cause within 24 weeks from study drug discontinuation), whichever occurred first.