ASCO 2018: Results for 2nd-line Therapy: A Cross-over Trial, Abiraterone + Prednisone vs Enzalutamide for Patients Metastatic Castration-Resistant Prostate Cancer

Chicago, IL ( Enzalutamide and abiraterone have both been established as oral antiandrogen therapies which prolong overall survival in men with metastatic castration-resistant prostate cancer1,2. However, for patients who receive enzalutamide or abiraterone as first line therapy, only 15-30% of patients will respond to the alternate therapy, demonstrating that there is significant cross-resistance which occurs between enzalutamide and abiraterone3. In a review by Dr. Emmanuel Antonarakis, three main categories of resistance are described: reactivation of persistent activation of the androgen receptor, androgen receptor bypass pathways, and androgen/androgen receptor independent mechanisms3. Many different strategies are being explored to overcome resistance but one such strategy is designing the optimal sequence of these two therapies to reduce acquired resistance, which this study prospectively examines.

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


1. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 2012;367:1187-97.
2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England journal of medicine 2011;364:1995-2005.
3. Antonarakis ES. Current understanding of resistance to abiraterone and enzalutamide in advanced prostate cancer. Clinical Advances in Hematology and Oncology 2016;14:316-9.

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