Lower Testosterone level and metastases-free survival in nmCRPC patients treated with novel antiandrogens: A post-hoc analysis of SPARTAN and ARAMIS

The EAU guidelines and the latest recommendations from the US Prostate Cancer Conference suggest a castration threshold of 20 ng/dl. However, the current NCCN and AUA guidelines still recommend a castration standard of 50 ng/dl. It remains unknown whether there is a relationship between maintaining lower testosterone levels and the prognosis of non-metastatic CRPC patients. We conducted a retrospective analysis based on two phase III clinical trials (SPARTAN - NCT01946204, ARAMIS - NCT02200614). Patients received the currently recommended first-line treatment regimens (ADT+apalutamide in SPARTAN and ADT+darolutamide in ARAMIS) were classified into two groups according to their maintenance levels of serum testosterone during treatment: below 20 ng/dl and above 20 ng/dl. The study endpoint was Metastasis-Free Survival (MFS). Inverse probability of treatment weighting (IPTW) method was employed to balance patients' baseline characteristics. Kaplan-Meier analysis, multivariable Cox regression models, and Cox models that included testosterone levels as a time-dependent covariate were utilized to investigate the influence of maintenance levels of serum testosterone on MFS. Baseline characteristics were well balanced between the low testosterone group and the high testosterone group after applying IPTW weights. Kaplan-Meier analysis indicated that there was no statistically significant association between serum testosterone levels and MFS in either trial. In both multivariable Cox regression models and time-dependent Cox regression models, the relationship between serum testosterone levels and MFS did not show statistical significance either, using below 20 ng/dl as the reference group (multivariable Cox: SPARTAN HR, 0.68 [95% CI, 0.47-0.98; P < 0.05], ARAMIS HR, 0.83 [95% CI, 0.57-1.20; P = 0.320]; time-dependent Cox: SPARTAN HR, 0.84 [95% CI, 0.68-1.04; P = 0.110], ARAMIS HR, 1.21 [95% CI, 0.71-2.08; P = 0.480]). The results obtained by setting testosterone levels as a continuous variable were similar. Among all men with testosterone < 50 ng/dl, maintenance serum testosterone levels >/= 20 ng/dl were not associated with poorer MFS in the first line therapy of nmCRPC with NHTs. The prognostic value of maintaining testosterone levels <20 ng/dl in patients with nmCRPC is limited and further treatment intensification is not indicated.