Michael J. Morris, MD

As reported in the Journal of Clinical Oncology by Michael J. Morris, MD, and colleagues, the phase III Alliance A031201 trial has shown no significant improvement in overall survival with the addition of abiraterone acetate and prednisone to enzalutamide as first-line treatment for metastatic castration-resistant prostate cancer.

Study Details

In the open-label trial, 1,311 patients from National Clinical Trials Network sites were randomly assigned between January 2014 and August 2016 to receive enzalutamide plus abiraterone acetate/prednisone (n = 654) or enzalutamide alone (n = 657). Treatment consisted of enzalutamide at 160 mg once daily, abiraterone acetate at 1,000 mg once daily, and prednisone at 5 mg twice daily. The primary endpoint was overall survival, with a significance level of P = .02.

Overall Survival

Median follow-up among surviving patients was 60.6 months (interquartile range = 38.9–63.0 months). Median overall survival was 34.2 months (95% confidence interval [CI] = 31.4–37.3 months) in the enzalutamide plus abiraterone acetate/prednisone group vs 32.7 months (95% CI = 30.5–35.4 months) in the enzalutamide-alone group (hazard ratio [HR] = 0.89, 95% CI = 0.78–1.01, P = .03, missing the significance level of .02).

Pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.

Median radiographic progression-free survival was 24.3 months (95% CI = 22.3–26.7 months) in the enzalutamide plus abiraterone acetate/prednisone group vs 21.3 months (95% CI = 19.4–22.9 months) in the enzalutamide-alone group (HR = 0.86, 95% CI = 0.76–0.97, P = .02).

Decreases in prostate-specific antigen of ≥ 50% were observed in 81% of the enzalutamide plus abiraterone acetate/prednisone group vs 82% of the enzalutamide-alone group, and ≥ 80% decreases were observed in 64% vs 62%.

Adverse Events

Grade ≥ 3 nonhematologic toxicity occurred in 69% of the enzalutamide plus abiraterone acetate/prednisone group vs 55% of the enzalutamide-alone group, including hypertension in 31% vs 22%, fatigue in 11% vs 6%, and transaminitis in 9% vs 2%. Any-grade transaminitis (43% vs 19%) and atrial fibrillation (2% vs 1%) were also more common in the enzalutamide plus abiraterone acetate/prednisone group. Any-grade arthralgia was less common in the enzalutamide plus abiraterone acetate/prednisone group (36% vs 45%), likely reflecting the use of prednisone. Any-grade seizure occurred in < 1% of each group.

The investigators concluded: “The addition of [abiraterone acetate/prednisone] to enzalutamide for first-line treatment of [metastatic castration-resistant prostate cancer] was not associated with a statistically significant benefit in [overall survival]. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.”

Dr. Morris, of Memorial Sloan Kettering Cancer Center, Sidney Kimmel Center for Prostate and Urologic Cancers, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by National Cancer Institute grants and Astellas. For full disclosures of the study authors, visit ascopubs.org.