Androgen receptor status and its changes during prostate cancer treatments

Introduction: Metastatic prostate cancer (PCa) patients can benefit temporarily from androgen deprivation therapy and then become castration-resistant. Currently, there is not a validated sequence of therapies for metastatic castration-resistant prostate cancer patients (mCRPC). Chemotherapy with docetaxel and cabazitaxel or next generation anti-androgen treatments such as abiraterone or enzalutamide are the therapeutical options, whereas 177Lu-PSMA therapy is administered as compassioned used. No approved biomarkers able to predict treatment response in PCa clinical practice are available. Androgen receptor (AR) gene copy number (CN) status detected at baseline or during treatments in plasma DNA could be a good candidate because it is one of the main factor involved in PCa and is the target of therapies such as enzalutamide and abiraterone. Methods: digital PCR technology was used to assess AR copy number on plasma DNA of castration-resistant prostate cancer at baseline of docetaxel or cabazitaxel-treated patients and during treatment with enzalutamide or abiraterone. Baseline AR CN was correlated with overall survival (OS) and progression free survival (PFS) of docetaxel and cabazitaxel-treated patients. Association between AR changes during treatment and OS and PFS was evaluated in patients analyzed during treatment with enzalutamide or abiraterone. Digital PCR and next generation sequencing technologies were used to identify AR CN and germline mutations in patients treated with 177Lu-PSMA therapy. Results: Among 163 patients treated with docetaxel, 50 (31%) presented plasma AR CN gain. OS was significantly shorter in AR-gained versus AR-normal patients (hazard ratio [HR] 95% CI 1.08–2.39, p = 0.02). No significant difference was observed for PFS. Among 155 patients treated with cabazitaxel, 65 (41.9%) had AR CN gain. AR-gained patients presented a significantly shorter median PFS (4.0 versus 5.0 months, HR 1.47, 95%CI 1.05-2.07, P=0.026) and a trend for worse OS. Among 79 patients analyzed during enzalutamide and abiraterone treatments, 11 (14%) changed AR CN status from baseline time point and a significant association between AR variation and OS was found: patients changing AR CN from normal to gain status had a median OS of 19.8 months (95% CI 8.0 – 27.7) compared to patients with stable AR CN normal that presented a median OS of 22.7 months (95% CI 19.0 – 30.5), patients with stable AR CN gain had a median OS of 9.1 (95% CI 3.8 – 17.9) whereas patients changing AR CN from gain to normal status not reached (p = 0.001). No significant association was observed between AR CN changes and PFS (p = 0.141). Multivariable analyses suggest that plasma AR CN change was an independent negative prognostic factor. Among 40 patients treated with 177Lu-PSMA, 15 (37.5%) showed AR CN gain. Moreover, pathogenetic variants were found in ATM, BRCA2, PMS2 genes and BRIP1 deletion was found in a patient. Conclusion: Our study highlighted the prognostic role of AR CN in docetaxel and cabazitaxel treatment cohorts. We also found that plasma AR CN changes during enzalutamide or abiraterone treatments are associated with worse OS in metastatic CRPC and further underlined the prognostic role of AR CN at baseline of these treatments. Moreover, pathogenetic variants of genes involved in DNA repair were identified in patients treated with 177Lu-PSMA and AR CN status identified mCRPC resistant to 177Lu-PSMA. Larger prospective studies are warranted to confirm our results.