PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19)

Abstract

Purpose: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC.

Patients and methods: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion.

Results: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively).

Conclusion: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

FIG 1.

Flow diagram. Patient disposition from the date of study consent as of the date of database freeze for the first interim analysis. Six hundred forty-three patients were screened and 503 patients were randomly assigned. PSA, prostate-specific antigen.

FIG 2.

PSA progression-free survival. (A) PSA-PFS, measured from the date of randomization, among patients randomly assigned to receive ADT + apalutamide (blue curve) versus ADT alone (red curve). The addition of apalutamide to ADT significantly prolonged PSA-PFS compared with ADT alone (median, 24.9 [95% CI, 23.3 to 32.3] months for ADT + apalutamide v 20.3 [95% CI, 18.2 to 22.9] months for ADT; HR, 0.52 [95% CI, 0.35 to 0.77]; P = .00047). (B) PSA-PFS in patients randomly assigned to receive ADT + apalutamide + abiraterone acetate plus prednisone (gray curve) versus ADT alone (red curve). The addition of apalutamide + abiraterone acetate/prednisone significantly prolonged PSA-PFS compared with ADT alone (median, 26.0 [95% CI, 22.9 to 32.5] months for ADT + apalutamide + abiraterone acetate plus prednisone v 20.0 [95% CI, 18.2 to 22.5] months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .0008). (C) Forest plot indicating the hazard ratio for PSA-PFS along with 95% CI for each experimental arm versus control with respect to PSA doubling time at study entry (<3,3-9 months). A consistent benefit with respect to PSA-PFS was observed in both strata for both experimental arms versus control. N represents the sample size and n is the number of events. ADT, androgen-deprivation therapy; APA, apalutamide; HR, hazard ratio; LHRH, luteinizing hormone-releasing hormone; PFS, progression-free survival; PSA, prostate-specific antigen.

FIG 3.

Time to testosterone recovery. Monthly testosterone assessments were completed after the 12-month treatment period. There was no significant difference in time to testosterone recovery after treatment completion, accounting for competing risks, in patients randomly assigned to (A) ADT + apalutamide or (B) apalutamide + AAP compared with ADT alone. Among the testosterone-evaluable subpopulation, defined as those patients whose serum testosterone recovered to >50 ng/dL after treatment completion, PSA PFS was significant prolonged in patients randomly assigned to receive (C) ADT + apalutamide and (D) ADT + apalutamide + AAP versus ADT alone. (A and B) The cumulative incidence of testosterone recovery by treatment. (C and D) The Kaplan-Meier estimates of PSA PFS by treatment. AAP, abiraterone acetate plus prednisone; ADT, androgen-deprivation therapy; APA, apalutamide; LHRH, luteinizing hormone-releasing hormone; PFS, progression-free survival; PSA, prostate-specific antigen.