Relationship between apalutamide (APA) exposure and metastasis-free survival (MFS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from SPARTAN

Abstract

Background: The phase 3 SPARTANstudy evaluated the efficacy and safety of APA vs placebo (PBO) in men with high‐risk nmCRPC. Because dose reductions/interruptions for the management of AEs that occur during treatment can affect drug efficacy, this analysis sought to understand the relationship of APA pharmacokinetic exposure and the primary end point of SPARTAN, MFS. Methods: 1207 pts were randomized in a 2:1 ratio to APA 240 mg/d or PBO. APA levels, and that of its active metabolite N‐desmethyl APA (NAPA), were measured by a validated LC/MS/MS assay. APA and NAPA exposures were quantified as the area under the concentration‐time curve at steady state (AUC24) at the average daily dose received, up to the MFS event. Exposure levels were evaluated as quartiles or continuous variables. Univariate and multivariate Cox regression models evaluated the relationship between APA/NAPA exposure and MFS and were adjusted by pre‐specified stratification factors (prostate‐specific antigen doubling time, bone‐sparing agent use, locoregional disease status) and other potential prognostic factors (age, ECOG PS). Results: 1206 pts were included in the analysis. AEs led to dose reduction/interruption in 33% vs 19% of APA and PBO pts, respectively, with average daily dose of 225 mg (APA) vs 229 mg (PBO) in pts with dose reduction/interruption. Mean (coefficient of variation [CV]%) PK exposure levels measured as AUC24 for APA and NAPA, respectively, were 117 (24 CV%) μg'H/mL and 155 (17 CV%) μg'H/mL for APA‐treated pts without dose reductions/interruptions, and 112 (24 CV%) μg'H/mL and 148 (18 CV%) μg'H/mL for those with dose reductions/interruptions. MFS benefit was similar across the range of APA/NAPA exposures. In univariate and multivariate Cox regression models, no significant differences in the exposure‐MFS relationship were observed for APA and NAPA. Conclusions: 240 mg/d APA provided efficacious drug exposure for the majority of pts, including those who required dose reductions/interruptions due to AEs. The MFS benefit was similar across the range of APA exposure. Dose reductions/interruptions due to AEs did not reduce the efficacy of APA.