Comparing ARPIs: The Challenge of No Head-to-Head Trials

Physicians now have a range of choices for treating metastatic hormone-sensitive prostate cancer, with 4 distinct androgen receptor pathway inhibitors (ARPIs) available: enzalutamide, apalutamide, abiraterone, and darolutamide. All of these drugs are proven to be effective and have been shown to prolong life in this specific setting. However, a significant challenge for clinicians is the lack of head-to-head clinical trials. No randomized studies have directly compared these ARPIs against each other, leaving doctors without a clear, evidence-based hierarchy for their use. For instance, there is no trial that directly contrasts the efficacy or side effects of enzalutamide versus darolutamide.

The absence of direct comparisons makes it difficult to make informed treatment decisions based on both efficacy and safety. To overcome this limitation, researchers and clinicians employ alternative methodologies to evaluate the differential effects of these ARPIs. One such powerful statistical technique is the matching-adjusted indirect comparison (MAIC).

The MAIC is a sophisticated statistical approach that allows for an indirect comparison of treatments from different clinical trials. It works by statistically adjusting for differences in patient populations and other factors that could influence a study's outcome. The methodology involves weighting individual patient data from one trial to match the baseline characteristics of the patients in a different trial. This creates a "synthetic" trial population that is comparable to the other, allowing for a more reliable comparison of outcomes. By using MAIC, researchers can analyze various efficacy outcomes—such as overall survival, progression-free survival, or time to metastasis—and infer which treatment might be superior if a head-to-head trial were to be conducted.

This method is crucial for providing guidance in clinical practice when direct evidence is unavailable. While not a substitute for a randomized controlled trial, a MAIC provides the best possible evidence for making treatment decisions by helping to identify potential differences in effectiveness and safety profiles among the 4 ARPIs. This allows physicians to make more nuanced choices tailored to individual patient needs and characteristics.