Prior local therapy enhances apalutamide’s effect on metastasis-free survival

A secondary post hoc analysis of the phase III SPARTAN trial shows that patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who received prior prostate-directed local therapy (LT) had longer metastasis-free survival (MFS) when treated with apalutamide vs those without prior LT.

Preclinical studies suggest that exposure to prostate-directed LT may influence the efficacy of subsequent systemic therapy, including androgen receptor pathway inhibitors (ARPIs). However, there is insufficient clinical evidence to support this in patients with nmCRPC.

The addition of apalutamide (an ARPI) to androgen deprivation therapy (ADT) was previously shown to significantly improve MFS (hazard ratio [HR], 0.28; 95 percent confidence interval [CI], 0.23–0.35) and overall survival (OS) (73.9 vs 59.9 months; HR, 0.78; 95 percent CI, 0.64–0.96) in patients with nmCRPC in the phase III double-blind, placebo-controlled, randomized SPARTAN trial. [N Engl J Med 2018;378:1408-1418; Eur Urol 2021;79:150-158] In the present secondary post hoc analysis, the researchers sought to determine whether exposure to prior LT (ie, radical prostatectomy [RP], radiation therapy [RT], or both) had a bearing on apalutamide’s treatment effect on MFS and OS. [JAMA Netw Open 2024;7:e2439434]

Of the 1,179 evaluable patients included in the analysis, 789 received ADT plus apalutamide, while 390 received ADT plus placebo; 795 patients had prior LT (median age, 70 years) and 384 did not (median age, 75 years). At a median follow-up of 52.0 months, the researchers observed a difference in the adjusted association between ADT plus apalutamide and MFS among subgroups stratified by exposure to prior LT (p_interaction=0.009). “Treatment with ADT plus apalutamide was associated with a 78.0 percent reduction in risk for distant metastasis or death among patients with prior LT [adjusted HR, 0.22; 95 percent CI, 0.17–0.27], compared with a 65.0 percent reduction among those without prior LT [adjusted HR, 0.35; 95 percent CI, 0.25–0.51],” they reported.

Among patients with vs without prior RP, treatment with ADT plus apalutamide had a relatively more favourable effect on MFS (with: adjusted HR, 0.18; 95 percent CI, 0.13–0.24; without: adjusted HR, 0.29; 95 percent CI, 0.23–0.37; p_interaction=0.005). Treatment with ADT plus apalutamide was associated with improved MFS in both subgroups with and without prior RT (with: adjusted HR, 0.22; 95 percent CI, 0.17–0.28; without: adjusted HR, 0.30; 95 percent CI, 0.22–0.40), but the difference was not significant.

There was no significant difference in the adjusted association between ADT plus apalutamide and OS among subgroups stratified by exposure to prior LT. “The lack of effect modification for OS may potentially reflect the effect of crossover to ADT plus apalutamide after distant metastasis for patients initially treated with ADT alone, thus diluting any substantive differential treatment effect. Furthermore, exposure to prior LT may be a surrogate for better access to treatment, lower-risk disease, superior overall performance status, and functional reserve,” suggested the researchers. [N Engl J Med 2013;368:436-445; J Urol 2004;171:1504-1507]