In this multicenter trial, 202 patients were randomized to abiraterone followed by enzalutamide (arm A) or the reverse (arm B). At the time of this report, in Arm A, 65 patients switched over from abiraterone to enzalutamide during the study, and in arm B, 71 patients switched from enzalutamide to abiraterone. A few characteristics were statistically different between the two arms. First, ECOG performance status was 0-1 in 89% of arm A, but only 76% in arm B (p = 0.044). Second, the LDH was above the upper limit of normal in 25% of arm A and only 8% of arm B (P=0.013).
The primary endpoints in this study was PSA decline by more than 50% on second line therapy (PSA50) and time to second PSA progression from the start of first line therapy (TT2P). Arm A (Abiraterone followed by enzalutamide) had a great percentage of PSA50 (34% vs 4%, p<0.001) as well as a slightly longer median time to PSA progression on second line therapy (2.7 months vs 1.3 months, HR 0.38, 95% CI 0.26-0.56). Not surprisingly, bone metastases and liver metastases were associated with a shorter time to progression on second line therapy. Deep-targeted sequencing of serial samples of circulating tumor DNA (ctDNA) was performed and a ctDNA fraction ≥ 2% was also associated with worse time to second progression (HR 2.04, 95% CI 1.43 - 2.90) and overall survival (HR 4.07, 95% CI 2.40-6.91). There were also genomic alterations which were associated with worse response including BRCA2/ATM truncating mutations, TP53 defects, and AR amplification. SPOP was associated with better outcomes.
Differences in median overall survival (Not reached in arm A vs 24.3 months in arm B, HR 0.82, 95% CI 0.53-1.27) did not reach significance but trended towards improved OS in arm A. This is interesting as patients in arm A appeared to have more advanced disease given the differences in ECOG and higher LDH.
During the poster discussion session, Simpa S. Salami, MD, MPH noted that “no significant difference [in OS] exists between the treatment arms. Based on this data alone, we are unable to recommend one sequence over another.” However, it did demonstrate that if you sequence your therapy with abiraterone first, it is not unreasonable to try enzalutamide as 34% of patients did have a response. Further studies are necessary to determine the ideal sequencing of these anti-androgen therapies. Clinical Trial Information NCT: NCT02125357
Presented by: Daniel Khalaf, MD, British Columbia Cancer Agency, Vancouver Centre.
Poster Discussion: Simpa S. Salami, MD, MPH
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Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA