Enzalutamide Plus Abiraterone Not Recommended for Patients With Metastatic Castration-Resistant Prostate Cancer

According to results from a phase 3 trial, the addition of abiraterone acetate and prednisone to enzalutamide for metastatic castration-resistant prostate cancer in the first-line setting was not associated with a statistically significant benefit to overall survival.

Lead investigator Michael J Morris, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and coauthors wrote, “The mechanism of action of enzalutamide and abiraterone are different, and each is well suited to address the resistance mechanisms associated with the other.”

In this study, it was hypothesized that abiraterone plus enzalutamide compared to enzalutamide alone would result in progression-free survival (PFS) and overall survival (OS) benefits, that there would be no drug-drug interactions (based on previous phase 1 data).

The study enrolled 1311 patients with untreated metastatic castration-resistant prostate cancer. Patients were randomized on a 1-to-1 basis to receive either 160mg of enzalutamide daily (enzalutamide arm, n = 657) or enzalutamide plus 1000mg of abiraterone once daily and 5mg prednisone twice daily (combination arm, n = 654). Randomization was stratified by previous exposure to chemotherapy and prognostic risk groups. The primary objective was a comparison of OS between the 2 treatment groups. Also examined were toxicity, radiographic PFS (rPFS), and pharmacokinetics.

Of the 389 surviving patients, the median follow-up duration was 60.6 months. There were 488 deaths in the enzalutamide arm and 434 deaths in the combination arm. The median OS in the enzalutamide arm was 32.7 months compared with 34.2 months in the combination arm. This did not represent a statistically significant difference (hazard ratio [HR]: 0.89; one-sided P = .03). There were 506 patients who experienced radiographic progression, and 489 patients died without experiencing radiographic progression. The combination arm had a median rPFS of 24.3 months, which was superior to the enzalutamide arm (21.3 months; HR: 0.86; one-sided P = .02). However, when the definition of progression was expanded to include clinical progression, the median rPFS of the enzalutamide arm was 16.9 months vs 20.1 months in the combination arm, which did not represent a change in effect (HR: 0.87). Additionally, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when combined with enzalutamide, compared to the clearance values of abiraterone alone.

In both study arms, the treatment was well-tolerated by most patients. The incidence of high-grade nonhematological toxicity, fatigue, hypertension, all-grade atrial fibrillation, and transaminitis were higher in the combination arm, consistent with the known profile of abiraterone. The incidence of all-grade arthralgia was higher in the enzalutamide arm.

Dr Morris et al concluded the combination of an enzalutamide plus abiraterone acetate and prednisone for patients with metastatic castration-resistant prostate cancer in the first-line setting “does not significantly prolong OS. The results related to our secondary end points also do not support combination therapy.” They added, “The combination was associated with an unfavorable drug-drug interaction that increased abiraterone clearance and with more adverse events.”

Journal of Clinical Oncology associate editor, Michael A Carducci, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, wrote that this trial “has been long awaited and affirms current practice supporting single-agent androgen receptor signaling inhibitors as standard of care for metastatic castration-sensitive prostate cancer.”

Source:

Morris MJ, Heller G, Hillman DW, et al. Randomized phase III study of enzalutamide compared with enzalutamide plus abiraterone for metastatic castration-resistant prostate cancer (Alliance A031201 Trial). J Clin Oncol. Published online: March 30, 2023. doi:10.1200/JCO.22.02394