What Is the AFFIRM Trial?

The AFFIRM trial (A Study Evaluating the Efficacy and Safety of Investigational Drug MDV3100) was a landmark Phase 3 clinical trial that investigated enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel chemotherapy. This international, randomized, double-blind, placebo-controlled study enrolled 1,199 patients across multiple centers.

Patients were randomly assigned in a 2:1 ratio to receive either oral enzalutamide at a dose of 160 mg per day or placebo. The primary endpoint of the study was overall survival, with secondary endpoints including radiographic progression-free survival, time to PSA progression, and quality-of-life measurements. The results of this trial fundamentally changed the treatment landscape for advanced prostate cancer patients.

How Enzalutamide Works

Enzalutamide belongs to a class of medications known as androgen receptor inhibitors. It works by targeting multiple steps in the androgen receptor signaling pathway, which plays a crucial role in prostate cancer growth and proliferation. Unlike earlier anti-androgens, enzalutamide has a higher affinity for the androgen receptor and prevents nuclear translocation of the receptor.

The medication blocks androgen binding to androgen receptors, inhibits androgen receptor nuclear translocation, and impairs binding of the androgen receptor to DNA. This triple mechanism of action effectively prevents androgen-dependent gene expression, ultimately leading to cancer cell death. This comprehensive approach to blocking androgen signaling explains why enzalutamide demonstrated significant efficacy in the AFFIRM trial even in patients whose disease had progressed after chemotherapy.

Key AFFIRM Trial Results

The AFFIRM trial results were groundbreaking, demonstrating a significant survival benefit for enzalutamide compared to placebo. The median overall survival was 18.4 months in the enzalutamide group versus 13.6 months in the placebo group, representing a 37% reduction in the risk of death. This survival advantage led to the trial being stopped early after a planned interim analysis showed clear benefit.

Beyond overall survival, enzalutamide showed improvements in all secondary endpoints. The time to PSA progression was 8.3 months with enzalutamide versus 3.0 months with placebo. Radiographic progression-free survival was 8.3 months versus 2.9 months, respectively. Additionally, 54% of patients receiving enzalutamide experienced a decline in PSA level of 50% or more, compared with just 2% in the placebo group. These results firmly established enzalutamide as an effective treatment option for men with mCRPC who had progressed after docetaxel therapy.

Provider Comparison for Enzalutamide Treatment

Several pharmaceutical companies are involved in the production and development of enzalutamide and similar treatments for advanced prostate cancer. The table below compares the key providers:

Provider Product Approval Status Key Features
Astellas Pharma Xtandi (enzalutamide) FDA approved Co-developer of enzalutamide, global distribution
Pfizer Xtandi (enzalutamide) FDA approved Co-marketing with Astellas after acquisition of Medivation
Janssen Pharmaceuticals Erleada (apalutamide) FDA approved Similar mechanism of action to enzalutamide
Bayer Nubeqa (darolutamide) FDA approved Newer androgen receptor inhibitor with different structure

Astellas Pharma and Pfizer jointly market Xtandi (enzalutamide) following Pfizer's acquisition of Medivation, the original co-developer. While all these medications work as androgen receptor inhibitors, they have subtle differences in their molecular structures, side effect profiles, and specific indications. Patients should work with their healthcare providers to determine which option might be most appropriate for their specific situation.

Benefits and Limitations of Enzalutamide

The AFFIRM trial highlighted several key benefits of enzalutamide treatment. Beyond extending overall survival, patients experienced improved quality of life measures and delayed disease progression. The oral administration route allows for convenient at-home dosing without the need for clinic visits for infusions. Additionally, enzalutamide demonstrated efficacy regardless of age, baseline pain intensity, geographic region, or type of disease progression at study entry.

However, there are important limitations to consider. Side effects reported in the AFFIRM trial included fatigue (34%), diarrhea (21%), hot flashes (20%), and headache (12%). More serious adverse events included seizures, which occurred in 0.6% of enzalutamide-treated patients. The medication also carries warnings about posterior reversible encephalopathy syndrome and hypersensitivity reactions. Some patients develop resistance to enzalutamide over time, and the drug is contraindicated in certain populations. A National Cancer Institute analysis suggests that combination therapies may be needed to overcome resistance mechanisms.

Conclusion

The AFFIRM trial established enzalutamide as a significant advancement in the treatment of metastatic castration-resistant prostate cancer, demonstrating meaningful survival benefits for men who had previously received docetaxel chemotherapy. This landmark study led to regulatory approval and has influenced clinical practice guidelines worldwide. Since the AFFIRM trial, additional studies have expanded enzalutamide's indications to earlier disease states, including non-metastatic castration-resistant prostate cancer and hormone-sensitive metastatic disease. As research continues, the role of enzalutamide in prostate cancer treatment continues to evolve, with ongoing investigations into combination approaches and biomarkers that may predict response to therapy. For patients with advanced prostate cancer, the results of the AFFIRM trial represent a meaningful therapeutic option that can extend survival and maintain quality of life.

Citations

This content was written by AI and reviewed by a human for quality and compliance.