Blood-based markers of differential efficacy of bipolar androgen therapy and enzalutamide in the randomized TRANSFORMER trial.
Authors: Denmeade Samuel R. , Antonarakis Emmanuel S. , Paller Channing Judith , Markowski Mark Christopher , Marshall Catherine Handy , Wang Hao , Tsai Hua-Ling , Kanayama Mayuko , Lu Changxue , Rabizadeh Daniel , Schumacher Megan , Luo Jun 
Published: June 2024

LBA5014

Background: Bipolar androgen therapy (BAT) for metastatic castration-resistant prostate cancer (mCRPC) is administered by alternating between supraphysiologic and near-castrate serum testosterone levels through intramuscular administration of testosterone cypionate 400mg given every 28 days together with ongoing androgen suppression. BAT is effective in a subset of patients, but evidence for predictive treatment selection is lacking. The goal of the study is to determine whether blood-based markers can be identified in the TRANSFORMER study, a randomized trial of abiraterone-pretreated mCRPC patients assigned to BAT or enzalutamide (Enza). Methods: We conducted whole genome and whole exome sequencing of circulating tumor DNA samples collected from the TRANSFORMER study. In this post-hoc biomarker study of a randomized trial, we sought to identify markers that predict preferential benefit from BAT or Enza in mCRPC patients progressing on abiraterone. We compared clinical or radiographic progression-free survival (PFS) and overall survival (OS) between BAT and Enza arms in subgroups defined by biomarker status and estimated treatment effects via the Cox regression model, stratified by duration of prior abiraterone treatment. To determine whether a molecular event is a predictive biomarker, we tested the interaction term of the dichotomized marker status by treatment arms. Statistical tests were two-sided, and p values ≤ 0.05 were deemed to indicate statistical significance. Results: We focused on somatic alterations implicated in androgen receptor (AR) signaling that can be detected at a relatively high frequency in blood samples. Whole genome sequencing and whole exome sequencing of cell-free DNA from 62 patients revealed tumor-specific AR pathway alterations, including AR point mutations and amplifications (33/62, 53.2%). In men with positive AR alterations detected in blood, BAT was more efficacious than Enza (median PFS 4.2 months vs. 2.9 months; hazard ratio [HR] 0.59[95% CI 0.25-1.37], P=0.22), while Enza was superior to BAT in those without AR alterations (median PFS 8.4 months vs. 3 months; HR 3.62[95%CI 1.44-9.1], P=0.006). We detected a significant interaction between AR alteration status and treatment types using PFS as the endpoint ( Pinteraction=0.002). The differential benefit is upheld with OS as the endpoint ( Pinteraction <0.001). In men with positive AR alterations, OS was longer with BAT compared with Enza (median OS 29.6 months vs. 24.1 months; HR 0.41[95% CI 0.16-1.03], P=0.058). In contrast, in men without AR alterations, OS was worse with BAT compared with Enza (median OS 19.3 months vs. NR; HR 4.38[95% CI 1.21-15.89], P=0.025). Conclusions: Metastatic CRPC patients progressing on abiraterone with AR alterations detected in blood may benefit preferentially from BAT. Routine liquid biopsy testing may enable further adoption of BAT.