However, in the past two years, three agents (apalutamide, enzalutamide, and darolutamide) have received FDA approval in this disease space due to their proven ability to prolong the time from castration-resistance to the development of metastasis (metastasis-free survival, MFS). In each case, these agents were compared to placebo and demonstrated benefit. However, due to the lack of active treatment comparisons, such a research approach fails to adequately inform clinicians and patients who must decide on a single agent (not a treatment class or strategy).
In contrast to a qualitative synthesis that informs most guidelines, network meta-analysis offers a quantitative approach to cross-trial comparisons. Network meta-analysis utilizes linked direct meta-analyses with a common comparator to allow for quantitative estimates of comparative treatment effects for agents that have not been directly compared in clinical trials. While direct evidence, and even more so meta-analysis of direct evidence, has typically been preferred in guideline writing, the World Health Organization has adopted network meta-analysis to inform clinical guidelines. Some have even suggested that network meta-analysis should supplant direct meta-analysis of randomized trials as the highest level of medical evidence to inform clinical decision making.1 With this in mind, we undertook a network meta-analysis of agents that have received FDA approval for nmCRPC.
We first examined this in a paper published in European Urology Oncology in 2018 at which time PROSPER (examining enzalutamide) and SPARTAN (examining apalutamide) had been presented.2 Utilizing an indirect comparison of these two agents, we found no evidence of a significant difference in MFS (hazard ratio 1.04, 95% confidence interval 0.78-1.37) between enzalutamide and apalutamide. Similarly, we found no difference in secondary outcomes including prostate-specific antigen progression, overall survival, and adverse events.
Since the publication of that analysis, the ARAMIS study reported outcomes for patients treated with darolutamide in this disease space. Thus, we updated our analysis accounting for this new data.3
Utilizing the data from these three trials, as expected, we found significantly improved MFS, PSA-PFS (prostate-specific antigen progression-free survival), and overall survival (OS) for patients who received nonsteroidal antiandrogen (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). Interestingly, subgroup analysis demonstrated a greater benefit with NSAAs in men with Eastern Cooperative Oncology Group (ECOG) performance status 0 (HR, 0.30; 95% CI, 0.24-0.38) versus 1 (HR, 0.45; 95% CI, 0.36-0.56; pheterogeneity = .005), but no difference owing to PSA doubling time (pheterogeneity = .43) or use of osteoclast targeting therapy (pheterogeneity = .77).
Following this pooled analysis, we then undertook network meta-analysis to compare the three agents: using a Bayesian approach, we found that 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.
While direct randomized controlled trials of these agents would be preferable to guide therapeutic decision making, to our knowledge, none are planned. Thus, these data may be useful to guide treatment choice. However, ongoing post-marketing surveillance (Phase IV studies) are required to assess the effectiveness (rather than ideal efficacy) of these agents in real-world practice.
Written by: Christopher J.D. Wallis, MD, PhD, Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee; Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia
References:
- Faltinsen, Erlend G., Ole Jakob Storebø, Janus C. Jakobsen, Kim Boesen, Theis Lange, and Christian Gluud. "Network meta-analysis: the highest level of medical evidence?." BMJ evidence-based medicine 23, no. 2 (2018): 56-59.
- Wallis, Christopher JD, Thenappan Chandrasekar, Hanan Goldberg, Laurence Klotz, Neil Fleshner, Raj Satkunasivam, and Zachary Klaassen. "Advanced androgen blockage in nonmetastatic castration-resistant prostate cancer: an indirect comparison of apalutamide and enzalutamide." European urology oncology 1, no. 3 (2018): 238-241.
- Hird, Amanda E., Diana E. Magee, Bimal Bhindi, Y. Ye Xiang, Thenappan Chandrasekar, Hanan Goldberg, Laurence Klotz et al. "A Systematic Review and Network Meta-Analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-Resistant Prostate Cancer." Clinical Genitourinary Cancer (2020).