New real-world studies suggest that the androgen receptor pathway inhibitor apalutamide (Erleada) may offer a survival advantage over two widely used alternatives, abiraterone acetate (Zytiga) and enzalutamide (Xtandi), for patients with metastatic castration-sensitive prostate cancer (mCSPC). The findings come at a time when clinicians lack head-to-head phase 3 trials to guide treatment decisions among the available therapies, leaving a critical evidence gap in the field.

Led by Dr. Mehmet A. Bilen, researchers analyzed data from nearly 4,000 patients treated at community-based urology practices across the United States. These studies employed advanced statistical methods to adjust for patient differences and reduce bias, including inverse probability of treatment weighting and alignment with updated FDA guidance.

The results were striking: apalutamide was associated with a 26% reduction in the risk of death at 24 months compared to abiraterone, and a 23% reduction compared to enzalutamide. These benefits persisted with longer follow-up, with more patients alive at 28 months and beyond in the apalutamide group. Unlike many clinical trials, the real-world cohorts included approximately 23% of patients identifying as Black or African American—an important step toward addressing longstanding disparities in prostate cancer research.

The studies arrive at a time when treatment choices for mCSPC are increasingly influenced by a wide range of real-world factors, such as comorbidities, drug interactions, quality of life, and insurance coverage. Without direct clinical trial comparisons, physicians have had to rely on individual patient characteristics to select therapies. These new findings offer much-needed data to help inform those choices, particularly in diverse, older populations that are typically underrepresented in randomized trials.

However, one notable limitation remains: the absence of a real-world or clinical trial comparison between apalutamide and darolutamide (Nubeqa), the fourth major ARPI approved for mCSPC. As darolutamide becomes more widely adopted, especially given its favorable safety profile, a head-to-head analysis will be important to fully understand its relative effectiveness in everyday practice.

While the methodology was rigorous, the authors acknowledge limitations inherent in real-world data. Adherence, side effects, and patient-reported outcomes were not comprehensively captured, and residual confounding cannot be ruled out. Nonetheless, the results are expected to influence clinical discussions, especially in settings where randomized data are lacking.

Further research is already underway. Investigators plan to analyze subgroups based on PSA levels, visceral metastases, comorbidities, and racial and ethnic backgrounds. Comparisons with darolutamide and other emerging therapies are also in development, along with efforts to factor in toxicity and tolerability alongside survival outcomes.

As the field of prostate cancer treatment evolves—with phase 3 trials exploring triplet therapies, biomarker-guided approaches, and novel combinations—real-world studies like these are playing an increasingly important role. For now, apalutamide appears to be emerging as a strong candidate for improving survival in patients with mCSPC, at least outside the confines of randomized trials.

Source.