Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

Abstract

8 Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival compared with PBO + ADT. This exploratory analysis investigated potential biological signatures of pts with long-term responses to APA and PBO. Methods: The biomarker cohort of SPARTAN was characterized as long-term responders (LTR) or early progressors (EP) based on time to metastasis, and separated into quartiles for APA and PBO groups. Pts progressing in the first quartile (APA, 21; PBO, 17), with shortest time to metastatic event, were classified as EP, those progressing in the last quartile (APA, 39; PBO, 20) as LTR. Gene expression profiles were generated from 233 archival primary prostate tumors. Predefined gene signatures indicative of cancer biology were compared between LTR and EP groups within the APA and PBO arms using 2 sample t tests. Signatures associated with LTR and EP were identified using p values of less than 0.05. Results: Median time to metastatic progression was 40.5 months in APA pts and 22 months in PBO pts in the LTR group and 7.3 and 3.6 months in APA and PBO pts, respectively, in the EP group. Signatures categorized into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) associated with LTR on APA included increased T cell activity reflected by T cell activation ( p = 0.0045), stimulation ( p = 0.0642), cytokine response ( p = 0.0489), and interferon production (gamma response p = 0.0227 ), and decreased T cell exclusion ( p = 0.0652), low proliferative capacity ( p = 0.0435), and increased hormonal dependence ( p = 0.0485). High risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors ( p = 0.0125) were associated with early progression on treatment with PBO. Conclusions: Although the data require confirmation in larger studies, these molecular determinants may have utility in selecting pts with nmCRPC who may derive the most benefit from APA and other androgen signaling inhibitors. Clinical trial information: NCT01946204.