A randomized phase II cross-over study of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).

Abstract

5002 Background: ABI and ENZ are indicated as 1st line therapy for mCRPC but have not been directly compared. Optimal sequencing of these agents has not been prospectively evaluated and predictive biomarkers are lacking. Methods: Multicenter, phase 2 study randomizing treatment-naïve mCRPC pts to ABI vs ENZ, with cross over at PSA progression. Primary endpoints: response and time to PSA progression (TTPP, PCWG3 criteria) after 2nd line therapy. Reported here are secondary endpoints: PSA ≥50% decline (PSA50) from baseline, TTPP with 1stline therapy, and correlation with deep targeted sequencing of 73 mCRPC genes in circulating tumor DNA (ctDNA). Results: Accrual completed October 2016 with 202 pts randomized (ABI:ENZ = 101:101). Median follow-up 12.8 months. Baseline characteristics were similar between arms: median for age was 75 years (range 49-94), PSA 36.1 (1.7-2817), HGB 130 (89-165), ALK PHOS 105 (31-6600), LDH 207 (77-3098). ECOG PS was 0-1 in 83%, presence of metastases in bone/liver/lung in 83%/6%/10%. With 1stline therapy for ABI vs ENZ, PSA50 at 12 weeks was 53% vs 73% (P = 0.004), no PSA decline occurred in 21% vs 15% (P = 0.243), and median TTPP was 7.4 vs 8.0 months (HR = 0.88, 95% CI 0.61, 1.27). Baseline ctDNA fraction was >2% in 60% of patients, and associated with worse TTPP (HR 1.80, P=0.005). Baseline pathogenic ctDNA alterations in AR, TP53, RB1, and DNA repair (BRCA2, ATM) genes were associated with a shorter TTPP (univariate analysis: TABLE). On multivariate analysis including clinical factors, TP53 and BRCA2/ATM alterations remained significant (HR = 2.54 (95%CI 1.55-4.19) and HR = 2.68 (1.58-4.54)). Pts with a PSA increase as best response were enriched for alterations in DNA repair (P <0.001), TP53 (P = 0.005), RB1 (P = 0.04), and (in 1 pt) a genomically truncated AR. Conclusions: There was a difference in PSA response for 1stline ABI vs ENZ, but no difference for TTPP. Baseline pathogenic ctDNA alterations, particularly in TP53 and BRCA2, identify pts with poor outcomes. Clinical trial information: NCT02125357. [Table: see text]

Propensity score‐matched comparison of docetaxel and androgen receptor axis‐targeted agents in patients with castration‐resistant intraductal carcinoma of the prostate

“…We need to see the exact rationale behind using docetaxel, abiraterone, or enzalutamide. Although Chi et al conducted a Phase II crossover study of abiraterone vs enzalutamide for patients with metastatic CRPC, it is still uncertain as to which agent might be optimal for first‐line treatment. Thus, today, there is no apparent rationale about the indication criteria and we did not have enough patients to clarify this in the present study.…”

Treatment selection for men with metastatic prostate cancer who progress on upfront chemo‐hormonal therapy

“…In prostate cancer cell lines, both docetaxel, and cabazitaxel were shown to interfere with the androgen receptor signaling by sharing a common cellular effect. Moreover, although more patients received abiraterone than enzalutamide in the mCRPC setting, existing retrospective and prospective data suggests no difference in rPFS according to the type of sHT used …”

“…In prostate cancer cell lines, both docetaxel, and cabazitaxel were shown to interfere with the androgen receptor signaling by sharing a common cellular effect. Moreover, although more patients received abiraterone than enzalutamide in the mCRPC setting, existing retrospective and prospective data suggests no difference in rPFS according to the type of sHT used 27,28. Whether the difference in time to radiographic progression observed in favor of sHT were influenced by the small sample size of the two groups and the timing of restaging scans could not be determined.…”

New research in prostate cancer, ASCO 2017

“…6 A total of 200 patients with treatment-naïve mCRPC were randomized to AAP (at a dose of 1000/10 mg daily) or enzalutamide (160 mg daily) and were crossed over to the other therapy at progression. The primary objective was to compare response and time to PSA progression (TTPP) after…”

“…6 A total of 200 patients with treatment-naïve mCRPC were randomized to AAP (at a dose of 1000/10 mg daily) or enzalutamide (160 mg daily) and were crossed over to the other therapy at progression. The primary objective was to compare response and time to PSA progression (TTPP) after Results showed that, although the enzalutamide arm demonstrated a more substantial PSA response at 12 weeks (77% compared to 55%), there were no significant differences between arms with respect to TTPP in the first-line setting (AAP 7.4 months vs. enzalutamide 8.0 months; HR 0.88; 95% CI 0.61-1.27).…”