Survival Benefits of Androgen Receptor Signaling-Axis Inhibitor’s at The Cost of Adverse Event Occurrence: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Previous evidence directly evaluating the efficacy and safety of the treatment for castration-resistant prostate cancer (CRPC) by androgen receptor (AR) signaling-axis inhibitors was limited by the quantity of randomized controlled trials (RCT) and biased by non-RCTs. We aim to comprehensively assess the efficacy and safety of abiraterone and enzalutamide using only RCTs. Patients and methods: We systematically searched Pubmed, Embase, MEDLINE and ClinicalTrial.gov for RCTs providing data of treatment outcomes by AR inhibitors (abiraterone and enzalutamide). Pooled hazard ratios (HR) with 95%CI for survival benefits were calculated using STATA 12.0. Comparison of prostate-specific antigen (PSA) response rate, aggregated adverse event (AE) statistics, any grade AE, high-grade AE (grade ≥3), AE of special interest between the treatment and control groups were performed by RevMan 5.3 and STATA 12.0. Results: Eight eligible RCTs with 6296 patients were selected. Pooled HR were 0.72 for overall survival, 0.45 for radiographic progression-free survival and 0.36 for PSA PFS. AR inhibitors could significantly increase the rate of PSA response (OR=8.67, 95%CI 4.42-17.04) and AE occurrence (OR=1.98, 95%CI 1.46-2.68). The treatment group had a higher occurrence of any-grade fatigue (OR=1.34, 95%CI 1.20-1.49), back pain (OR=1.15, 95%CI 1.01-1.15), hot flush (OR=1.76, 95%CI 1.50-2.06), diarrhea (OR=1.22, 95%CI 1.07-2.40) and arthralgia (OR=1.34, 95%CI 1.16-1.54). Particularly, the outcomes for AEs of special interest including any grade hypertension (OR=2.06, 95%CI 1.71-2.47), hypokalemia (OR=1.80, 95%CI 1.42-2.30) and fluid retention or edema (OR=1.38, 95%CI 1.17-1.63) also favored the control group. In terms of high-grade AEs, a higher occurrence of hypertension (OR=2.60, 95%CI 1.79-3.79) and pain in extremity (OR=4.46, 95%CI 2.81-7.07) was observed in the treatment group. There was no significant difference regarding other AEs analyzed in this study. Conclusion: The survival benefits by AR inhibitors for CRPC were evident and promising at the cost of acceptably higher risk of AEs occurrence.