Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.

Abstract

5546 Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p<0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.