Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment

Abstract

Purpose Enzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO ( ClinicalTrials.gov identifier: NCT01995513) interrogated this hypothesis using a randomized, double-blind, placebo-controlled design. Patients and Methods In period one, men with chemotherapy-naïve metastatic castration-resistant prostate cancer received open-label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two. Results Of 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group. Conclusion Combining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy.

Fig 1.

(A) Scientific hypotheses underlying PLATO trial and (B) PLATO trial design. Actual patient numbers at each trial milestone are included on the bottom row of panel B, and target numbers are included in brackets. More details on period one patient disposition are provided in the Data Supplement. AR, androgen receptor; PFS, progression-free survival; PSA, prostate-specific antigen. (*) Random assignment was stratified by confirmed PSA response at week 13 in period one (≥ 0% to < 30% v ≥ 30%).

Fig 2.

Patient disposition in period two. ECOG PS, Eastern Cooperative Oncology Group performance status. (*) Reasons included clinical disease progression and rising prostate-specific antigen. (†) Reasons included rising prostate-specific antigen and disease metastasis.

Fig 3.

Kaplan-Meier estimates for progression-free survival (PFS). Dotted line represents median. HR, hazard ratio.

Fig 4.

(A) Best single prostate-specific antigen (PSA) change in period two and (B) Kaplan-Meier estimate for time to PSA progression. Dotted lines represent (A) PSA declines of 30%, 50%, and 90% and (B) median. HR, hazard ratio.