A Systematic Review and Network Meta-analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-resistant Prostate Cancer.

Among men with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC), we used network meta-analysis to compare non-steroidal anti-androgens (NSAAs) and stratified class-level meta-analysis to identify subgroups with particular benefit from NSAAs with androgen deprivation therapy versus androgen deprivation therapy alone.

We performed a systematic review of phase III parallel-group randomized controlled trials in adult men with nmCRPC. Primary outcome was metastasis-free survival (MFS). Secondary outcomes included overall survival (OS), prostate-specific antigen (PSA) progression-free survival (PFS), and rates of grade 3 to 4 adverse events (AEs). We assessed class-level effects using random effects models; effect modification owing to subgroup effects using random-effects models to pool study-level differences; and comparative outcomes between agents using fixed-effect network models in a Bayesian framework.

Three randomized controlled trials were identified. Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.25-0.41; HR, 0.08; 95% CI, 0.05-0.13; and HR, 0.74; 95% CI, 0.61-0.90, respectively). Subgroup analysis demonstrated a greater benefit with NSAAs in men with Eastern Cooperative Oncology Group performance status 0 (HR, 0.30; 95% CI, 0.24-0.38) versus 1 (HR, 0.45; 95% CI, 0.36-0.56; P = .005), but no difference owing to PSA doubling time (P = .43) or use of osteoclast targeting therapy (P = .77). Bayesian analysis showed apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively, with subgroup analysis demonstrating these agents were preferred regardless of PSA doubling time and performance status. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. Grade 3 to 4 AEs were more common with NSAAs (odds ratio [OR], 1.47; 95% CI, 1.27-1.71) and there was a 61% chance that darolutamide was preferred.

NSAAs improve survival in high-risk nmCRPC. Apalutamide and enzalutamide may result in improved oncologic outcomes. Darolutamide may result in fewer AEs. Phase IV data are needed to validate these findings.

Clinical genitourinary cancer. 2020 Mar 06 [Epub ahead of print]

Amanda E Hird, Diana E Magee, Bimal Bhindi, Xiang Y Ye, Thenappan Chandrasekar, Hanan Goldberg, Laurence Klotz, Neil Fleshner, Raj Satkunasivam, Zachary Klaassen, Christopher J D Wallis

Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada., Division of Urology, Department of Surgery, University of Calgary, Calgary, Alberta, Canada., MiCare Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada., Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA., Division of Urology, Department of Surgery, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada., Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada., Department of Urology and Center for Outcomes Research, Houston Methodist Hospital, Houston, TX., Division of Urology, Medical College of Georgia at Augusta University, Augusta, GA; Georgia Cancer Center, Augusta, GA., Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN. Electronic address: .