PARP1 and Androgen Receptor Inhibition in Metastatic Castration-Resistant Prostate Cancer
In a phase II trial (NCI 9012) reported in the Journal of Clinical Oncology, Hussain et al found no benefit of adding PARP1 inhibition with veliparib to abiraterone (Zytiga) plus prednisone in patients with metastatic castration-resistant prostate cancer. ETS fusion status was not predictive of response.
Study Details
In the study, 148 patents from 12 U.S. sites were randomly assigned between May 2012 and December 2015 to receive abiraterone plus prednisone with (n = 76) or without (n = 72) veliparib after metastatic site biopsy. Treatment consisted of abiraterone 1,000 mg/d plus prednisone 5 mg twice per day with or without veliparib 300 mg twice per day for days 1 to 28. Randomization was stratified by ETS status. The primary objectives were confirmed prostate-specific antigen (PSA) response rate and effect of ETS fusions on response. ETS fusions were present in 34% to 35% of patients.
Response Rates
The PSA response rate was 72.4% in the veliparib group vs 63.9% in the control group (P = .27). Measureable disease response rate was 52.2% vs 45.0% (P = .51). Median progression-free survival was 11.0 vs 10.1 months (P = .99). The presence of ETS fusions did not predict PSA or measureable disease response or progression-free survival.
Biomarker Analysis
Exploratory analysis of tumor sequencing in 80 patients showed that 51% were ETS-positive; 25% had DNA-damage repair defect (DRD); 51% had AR amplification or copy gain; 43% had PTEN mutation; 41% had TP53 mutation; 49% had PIK3CA pathway activation; and 15% had WNT pathway alteration. Compared with patients with wild-type tumors, those with DRD had improved PSA response rate (90% vs 56.7%, P = .007), measureable disease response rate (87.5% vs 38.6%, P = .001), PSA decline ≥ 90% (75% vs 25%, P = .001), and median progression-free survival (14.5 vs 8.1 months, P = .025). Compared with patients with mutation or pathway activation, those with normal PTEN (13.5 vs 6.7 months, P = .02), TP53 (13.5 vs 7.7 months, P = .01), and PIK3CA (13.8 vs 8.3 months, P = .03) had longer median progression-free survival.
The investigators concluded, “Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with [metastatic castration-resistant prostate cancer] outcomes.”
The study was supported by grants from the National Cancer Institute (NCI), Prostate Cancer Foundation, NCI Specialized Program of Research Excellence, and U.S. Department of Defense Mission Command Training Program.
Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, is the corresponding author for the Journal of Clinical Oncology article.
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