Citations

PURPOSE Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. PATIENTS AND METHODS Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments. RESULTS In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone. CONCLUSION The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. 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.

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .

5008 Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.