ARPI Choices Beyond Efficacy in Prostate Cancer

In the absence of direct, head-to-head randomized trials, making a definitive recommendation between androgen receptor pathway inhibitors (ARPIs) like enzalutamide and darolutamide remains a significant challenge for physicians. While a head-to-head trial would be the gold standard, it is highly unlikely to be conducted by the pharmaceutical industry, as there is little commercial incentive to directly compare two competing products. Therefore, the data from methodologies like the matching-adjusted indirect comparison (MAIC) become critically important.

The MAIC is not a replacement for a prospective, randomized study, but it offers a powerful way to statistically model what the results might be if such a trial were performed. The surprising findings from our MAIC, which showed enzalutamide providing a nearly 50% greater delay in radiographic progression-free survival (rPFS), could serve as a "provocative" data point. This could lay the groundwork for a future, real-world controlled study comparing these agents directly, although such a trial would likely take many years to complete.

In the interim, clinicians must rely on a more holistic approach to treatment decisions, where the MAIC-derived efficacy data is just one part of the equation. Other crucial factors must be considered, including the cost of the drugs, their availability to the patient, and their respective safety and toxicity profiles. Each patient presents a unique clinical picture, with individual comorbidities, age-related factors, and concurrent medications that can influence the choice of therapy. For example, a patient with a history of seizures might be a poor candidate for an ARPI known to have a higher risk of central nervous system (CNS) side effects, regardless of its efficacy.

This MAIC specifically focused on efficacy and did not analyze safety or toxicity signals. However, the safety profiles of both enzalutamide and darolutamide have been well-established in their respective pivotal trials, ARCHES and ARANOTE, as well as in other studies. For example, darolutamide has been noted for its lower propensity to cross the blood-brain barrier, which is believed to result in a more favorable central nervous system side effect profile, with lower rates of fatigue, falls, and cognitive impairment compared to other ARPIs. Conversely, enzalutamide has a higher reported incidence of these CNS-related adverse events.

Therefore, if maximizing efficacy is the primary goal for a patient and their physician, the MAIC data might lead them to favor enzalutamide. However, if the patient places a higher value on quality of life and avoiding certain side effects—such as fatigue, falls, or cognitive issues—darolutamide might be the preferred choice, even if its efficacy, based on this indirect comparison, appears to be slightly less. Ultimately, the decision-making process is a shared one between the patient and physician, balancing a complex set of factors to arrive at the most appropriate and personalized treatment plan.