For this study, patients had a biopsy of their metastatic disease, which was subsequently tested via immunohistochemistry and stratified by ETS status. Patients were then randomized 1:1 to abiraterone + prednisone (Arm A) or abiraterone + prednisone + veliparib (Arm B). The primary end point of the study was PSA response rate (RR ≥ 50% decline), and was powered to detect a 20% PSA RR improvement assuming a 5% 1-sided type I error and 80% power (n=148). Secondary endpoints included (i) safety, (ii) objective RR (ORR), (iii) progression free survival (PFS), and (iv) molecular analysis to assess if DNA repair gene deficiency (BRCA 1, BRCA 2, ATM, FANCA, PALB2, RAD51B, RAD51C) predicts response. There were 72 patients randomized to Arm A and 76 patients to Arm B. There was no difference between the groups regarding PSA RR (p=0.27), ORR (p=0.51) or median PFS (Arm A – 10.1 months vs Arm B 11.0 months, p=0.89), regardless of ETS status. Among 80 patients that underwent metastatic tissue genome sequencing, 53% were ETS positive, 25% had DNA repair gene deficiencies, 59% had AR amplification/copy gain, 40% had PTEN mutation, 41% had TP53 mutation, and 46% had PIK3CA activation. Irrespective of treatment arm, patients with DNA repair gene deficiencies had higher PSA and ORR (≥87%), higher PSA decline rate of ≥90%, and longer median PFS compared to the wild type genotype (14.5 vs 8.0 months, p=0.02). Using an elastic net multivariable Cox model adjusting for clinical factors, DNA repair gene deficiencies and normal PTEN, TP53 and PIK3CA were associated with PFS. The strength of this study was the ability to accrue patients to their target inclusion sample size, and the ability to integrate molecular analysis into this therapeutic trial.
In summary, the authors concluded that there was a non-statistically significant trend in favor of abiraterone/prednisone + veliparib, however there was no difference by ETS positivity. Patients with DNA repair gene deficiencies had better PSA response rate, measurable response rate, and median PFS compared to WT patients. Demonstrating the importance of DNA repair gene deficiencies and PTEN, TP53 and PIK3CA status in therapeutic trials sets the stage for designing and integrating genetic status into future clinical trials.
Clinical trial: NCT01576172
Presented By: Maha Hussain, Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
Co-Authors: Stephanie Daignault, Przemyslaw Twardowski, Costantine Albany, Mark N. Stein, Lakshmi Priya Kunju, Dan R. Robinson, Kathleen A. Cooney, Robert B. Montgomery, Emmanuel S. Antonarakis, Daniel H. Shevrin, Paul Gettys Corn, Young E. Whang, David C. Smith, Megan Veresh Caram, Scott A. Tomlins, Karen E. Knudsen, Walter Michael Stadler, Felix Yi-Chung Feng, Arul M. Chinnaiyan
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