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Enzalutamide enhances PSA response, but not time to PSA progression, vs. abiraterone

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CHICAGO – Enzalutamide demonstrated a greater PSA response among patients with metastatic, castration-resistant prostate cancer than abiraterone, although time to PSA progression was unchanged between the agents, according to a multicenter phase 2 crossover study presented at the ASCO Annual Meeting.

In addition, alterations in baseline pathogenic circulating tumor DNA, or ctDNA, including TP53 and BRCA2, were predictive of poor outcomes.

“[Abiraterone acetate (Zytiga, Janssen)] and [enzalutamide (Xtandi, Astellas)] are indicated as first-line therapy for patients with metastatic, castration-resistant prostate cancer, but have not been directly compared,” the researchers wrote. “Optimal sequencing of these agents has not been prospectively evaluated and predictive biomarkers are lacking.”

Kim Chi, MD, of the Vancouver Prostate Center and the British Columbia Cancer Agency, and colleagues randomly assigned previously untreated patients to abiraterone or enzalutamide, with crossover at the time of PSA progression. Response and time to PSA progression following second-line therapy served as the primary endpoints, but the results presented at ASCO focused on the secondary endpoints. These included a decline in PSA from baseline of greater than or equal to 50%, time to PSA progression with first-line therapy and correlations with deep targeted sequencing of 73 metastatic, castration-resistant prostate cancer genes in ctDNA.

Patients (n=202) were evenly divided into two therapeutic arms; the length of median follow-up was 12.8 months. Baseline characteristics were comparable between treatment groups. The following statistics were presented as the median: age, 75 years (range, 49-94); PSA, 36.1 (range, 1.7-2,817); HGB, 130 (range, 89-165), alkaline phosphatase, 105 (range, 31-6,600) and lactate dehydrogenase, 207 (range, 77-3,098). The ECOG performance status was 0 to 1 in 83% of patients and metastases in the bone, liver and lung were detected in 83%, 6% and 10% of patients, respectively.

More patients in the enzalutamide arm achieved a 50% or greater reduction in PSA by week 12 (73% with enzalutamide vs. 53% with abiraterone; P = .004). No decrease in PSA was seen in 15% of patients in the enzalutamide arm, compared with no decrease among 21% of patients in the abiraterone arm, although this was not significant (P = .243). Median time to PSA progression was 8 months among patients treated with enzalutamide vs. 7.4 months for those treated with abiraterone (HR, 0.88; 95% CI, 0.61-1.27).

The baseline ctDNA fraction was > 2% among 60% of patients and correlated with inferior time to PSA progression (HR, 1.80; P = .005). Baseline pathogenic ctDNA alterations in AR, TP53, RB1 and DNA repair (BRCA2 and ATM) genes correlated with less time to PSA progression. On multivariate analysis, including clinical factors, TP53 (HR, 2.54; 95% CI, 1.55-4.19) and BRCA2/ATM (HR, 2.68; 95% CI, 1.58-4.54) alterations continued to be significant. Participants who achieved “a PSA increase as best response were enriched for alterations in DNA repair (P < .001), TP53 (P = .005), RB1 (P = .04) and, in one patient, a genomically truncated AR,” according to the study results.

“There was a difference in PSA response for first-line abiraterone vs. enzalutamide, but no difference for time to PSA progression,” the researchers wrote. “Baseline pathogenic ctDNA alterations, particularly in TP53 and BRCA2, identify patients with poor outcomes.” - by Julia Ernst, MS

Reference:

Chi KN, et al. Abstract 5002. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Chi reports serving in a consultant or advisory role with Amgen, Astellas Pharma, Bayer, ESSA, Janssen, Lilly/ImClone, Sanofi and Takeda; receiving honoraria from Amgen, Astellas Pharma, Janssen and Sanofi; and receiving research funding through his institution from Amgen, Astellas Pharma, Bayer, Janssen, Lilly/ImClone, Novartis, Oncogenex, Sanofi, Teva and Tokai Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.