Is the Gleason score the driver for the treatment decision-making of patients with castration-resistant prostate cancer in the new era of the anti-androgenic therapies?

Fizazi et al. [1] showed the initial diagnostic Gleason score in patients with metastatic castration-resistant prostate cancer (mCRPC) should not be considered in the medical decision oriented to abiraterone. Based on these findings, we believe it would be important to extend the analyses carried out by Fizazi et al. to all novel anti-androgenic therapies with a pooled analysis of available trials from the literature. The studies were identified, according to the following inclusion criteria: (i) patients with mCRPC; (ii) a novel anti-androgenic therapy including the selective 17,20-lyase inhibitor orteronel; (iii) the presence of a control arm for comparison ( placebo or not); and (iv) the presence of data on overall survival (OS) and progression-free survival (PFS) according to the Gleason score. The following exclusion criteria were used: (i) insufficient data were available to estimate the outcomes; (ii) animal studies; (iii) the size of each arm was<10 participants; and (iv) non-randomized studies. The summary estimates were generated using a fixedeffect model (Mantel–Haenszel method) or a random-effect model (DerSimonian–Laird method) depending on the absence or presence of heterogeneity (I2). Seven studies were included in the analysis (Table 1), Gleason score of 8 was the cut-off for the analysis. ELM-PC 4, ELM-PC 5, COU-AA-301, COU-AA-302 and PREVAIL trials reported data on hazard ratio (HR) of OS (Table 1) according to the initial Gleason score. The AFFIRM trial was excluded because it does not report data on PFS and OS according to the Gleason score. In regard to OS, a total of 6187 cases were included; 2982 cases (1654 in the experimental and 1328 in the control arm) had Gleason score <8, while 3205 cases (1797 in the experimental and 1408 in the control arm) had Gleason score ≥8 (Table 1). The analysis according to the Gleason score revealed novel anti-androgenic therapies significantly improved OS with similar extent in patients with Gleason score <8 [HR = 0.82, 95% confidence interval (CI) 0.73–0.91; P = 0.0004] compared with performance Gleason score ≥8 (HR = 0.81, 95% CI 0.73– 0.90; P < 0.00001] (Figure 1A). The fixed-effects model was used for the analysis due to the moderate heterogeneity (I2 = 46%) between the trials.