P53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer

Background: We tested whether tissue-based analysis of p53 and PTEN genomic status in primary tumors is predictive for subsequent sensitivity to abiraterone and enzalutamide in castration-resistant prostate cancer (CRPC). Methods: We performed a retrospective analysis of 309 consecutive patients with CRPC treated with abiraterone or enzalutamide. Of these, 101 men (33%) had available primary tumor tissue for analysis. We screened for deleterious TP53 missense mutations and PTEN deletions using genetically validated immunohistochemical assays for nuclear accumulation of p53 protein and PTEN protein loss, with sequencing confirmation of TP53 mutations in a subset. Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without p53 and/or PTEN alterations. Results: Forty-eight percent of the evaluable cases had PTEN loss and 27% had p53 nuclear accumulation. OS and PFS did not differ according to PTEN status, but were significantly associated with p53 status. Median OS was 16.7 months (95% CI, 14-21.9 months) and 31.2 months (95% CI, 24.5-43.4) for men with and without p53 nuclear accumulation, respectively (HR 2.32; 95% CI 1.19-4.51; P = 0.0018). Similarly, median PFS was 5.5 months (95% CI, 3.2-9.9 months) and 10.9 months (95% CI, 8-15.2 months) in men with and without p53 nuclear accumulation, respectively (HR 2.14, 95%CI 1.20-3.81; P = 0.0008). In multivariable analyses, p53 status was independently associated with PFS (HR 2.15; 95% CI 1.03-4.49; P = 0.04) and a HR of 2.19 for OS (95% CI 0.89-5.40; P = 0.087). Conclusions: p53 inactivation in the primary tumor (but not PTEN loss) may be predictive of inferior outcomes to novel hormonal therapies in CRPC.