3.1 Study characteristics
From the 489 retrieved publications, we selected 84 potentially eligible articles for abstract and full articles review. Eventually 8 RCTs with 10 articles met the inclusion criteria6-10,17-21, which were published from 2012 to 2017(figure 1 and table 1). Two trials were phase 2, while six trials were phase 3. Five trials were conducted in first-line fashion and three with second-line (table 1). For each trial, the number of CRPC patients ranged from 196 to 1199, and a total of 6290 patients were included. 2804 patients (44.6%) were enrolled in abiraterone trials and 3486 (55.4%) in enzalutamide trials. The median age of enrolled patients varied from 68 to 74 with two trials reported mean ages.
The superiority of the experimental group over the control group was shown for PSA response (prostate-specific antigen level decline 50% or more from baseline) rate reported in seven studies. The rate of PSA decline ≥50% in the experimental group ranged from 5.1% to 90.9%. compared with 1.3% to 42.0% in the control group. The median overall survival was reported in four studies and the increased duration in the experimental group varied from 4.0 months to 4.6 months compared with the control group. Overall PFS, radiographic PFS and PSA PFS were reported asymmetrically in those trials. Still, the median PFS was generally longer in the AR inhibitor group regarding either overall PFS, radiographic PFS or PSA PFS.
3.2 Overall survival, progression-free survival and PSA response rate
Figure 2 presented the efficacy of abiraterone and enzalutamide among all the enrolled participants. HR with 95% CI for OS was assessed in five trials while HR with 95% CI for radiographic PFS and PSA PFS were both assessed in six trails. Patients treated with abiraterone and enzalutamide had greater survival benefits with pooled HR for OS (HR=0.72, 95% CI 0.67-0.78), radiographic PFS (HR=0.45, 95%CI 0.42-0.48) and PSA PFS (HR=0.36,95%CI 0.32-0.40), respectively. PSA response rate was evaluated in figure 3. Patients treated with AR inhibitors had a significantly higher rate of PSA response (OR=10.15, 95%CI 8.07-12.28, P<0.00001) than the control group did.
In addition, we also conducted a subgroup analysis according to the different type of AR inhibitor (supplementary figure s1, s2 and s3). It seemed enzalutamide had greater efficacy than abiraterone in either rPFS (HR: 0.36 vs 0.60, Pheterogeneity<0.05), PSA PFS (HR: 0.24 vs 0.57, Pheterogeneity<0.05) or PSA response rate (OR: 21.88 vs 4.69, Pheterogeneity<0.05), but not in overall survival (HR: 0.71 vs 0.78, Pheterogeneity=0.319).
3.3 Aggerated adverse events statistics
As figure 4 displayed, the AR inhibitor group had a higher probability of occurrence of any-grade AE (OR=1.98, 95%CI 1.46-2.68, P<0.0001). However, no significant difference was found between the treatment and control group in regard to occurrence of high-grade AE (grade≥3), AE leading to death, AE leading to discontinuation and any serious AE, even though the AR inhibitor group had a virtually significantly lower chance of high-grade AE (OR=0.91, 95% CI 0.82-1.01, P=0.08).
3.4 Any-grade adverse events
Figure 5A displayed any-grade AEs with significant difference between the AR inhibitor and control groups. As the forest plots showed, patients in the treatment group experienced higher rate of any-grade fatigue (OR=1.34, 95%CI 1.20-1.49, P<0.00001), back pain (OR=1.15, 95%CI 1.01-1.15, P=0.03), hot flush (OR=1.76, 95%CI 1.50-2.06, P<0.00001), diarrhea (OR=1.22, 95%CI 1.07-2.40, P=0.003), and arthralgia (OR=1.34, 95%CI 1.16-1.54, P<0.001). No significant difference was observed in constipation (OR=1.13, 95% CI 0.98-1.29, P=0.09) bone pain, pain in extremity, anemia, tract infection and nausea (supplementary figure S4).
Outcomes for AEs of special interest (Figure 5B), including any-grade hypertension (OR=2.06, 95%CI 1.71-2.47, P<0.00001), hypokalemia (OR=1.80, 95%CI 1.42-2.30, P<0.00001) and fluid retention or edema (OR=1.38, 95%CI 1.17-1.63, P=0.0001) all significantly favored the control group.
3.5 High-grade (grade ≥3) adverse events
In terms of high-grade AEs, a higher risk of hypertension (OR=2.60, 95%CI 1.79-3.79, P<0.00001) and pain in extremity (OR=4.46, 95%CI 2.81-7.07, P<0.00001) in the AR inhibitor group was observed (Figure 5C). There were no significant differences in high-grade fatigue, back pain, constipation, diarrhea, hot flush, fluid retention or edema, urinary tract infection, falls, or decreased appetite between the treatment and control groups. (supplementary figure S5)
3.6 Quality assessment
All trials employed randomized treatment allocation sequences, and three of them were computer-generated random number or using similar fashion. All trials were double blinded. Jadad scores were given to each trial and listed in table 2. The mean score was 4.25 and all trials were ranked as high quality.