For this study, the authors used a multicenter, phase II approach with inclusion criteria being treatment-naïve men with mCRPC. The study was designed for crossover treatment at the time of PSA progression; the primary endpoint was response and time to PSA progression (using PCWG3 criteria) after 2nd line therapy. Secondary outcomes included (i) PSA ≥50% decline from baseline, (ii) time to PSA progression with 1stline therapy, and (iii) correlation with deep targeted sequencing of 73 mCRPC genes in circulating tumor DNA (ctDNA). Through completion of accrual in October 2016, 202 patients were randomized 1:1 to receive either abiraterone + placebo vs enzalutamide, with a median follow-up of 12.8 months. At baseline, median age was 75 years (range 49-94), PSA 36.1 (1.7-2817), hemoglobin 130 (89-165), alkaline phosphatase 105 (31-6600), LDH 207 (77-3098), with the only difference between the two groups being age (abiraterone 72.9 vs enzalutamide 77.6 years, p=0.01). The presence of metastases to the bone, liver, and lung was 83%, 6%, and 10%, respectively. Patients taking first line enzalutamide had improved PSA ≥50% decline at 12 weeks (77%) compared to abiraterone (55%) (p=0.001). There was no difference between the groups with regards to percentage of patients having no PSA decline (enzalutamide 10% vs abiraterone 20%, p=0.0501), median time to PSA progression (enzalutamide 14.9 months vs abiraterone 10.2 months; HR 0.83, 95%CI 0.55-1.25), or time to progression (enzalutamide 7.4 months vs abiraterone 7.4 months; HR 0.82, 95%CI 0.58-1.16).
The ctDNA results demonstrated that a fraction >2% (in 60% of patients) was associated with worse time to PSA progression after 2nd line therapy (5.4 months vs non-quantifiable ctDNA 12.0 months; HR 2.05, 95%CI 1.42-2.96), as well as pathogenic alterations in AR, TP53, RB1, and DNA repair genes (BRCA2, ATM). In a multivariable model 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 remained significant predictors of shorter time to PSA progression after 2nd line therapy.
In summary, this is an important trial demonstrating that although patients taking enzalutamide had improved initial PSA response, there was no difference in time to PSA progression after 2nd line therapy compared to patients receiving abiraterone. Not surprisingly, ctDNA biomarkers suggest that patients with TP53 and BRCA2 alterations identify patients with a poor prognosis.
Clinical trial: NCT02125357
Presented By: Kim N. Chi, British Columbia Cancer Agency, Vancouver, BC, Canada
Co-Author(s): Matti Annala, Katherine Sunderland, Daniel Khalaf, Daygen Finch, Conrad D. Oja, Joanna Vergidis, Muhammad Zulfiqar, Kevin Beja, Gillian Vandekerkhove, Martin Gleave, Alexander William Wyatt
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA