Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide

Abstract

Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.

Fig 1.

Clinical outcomes in the overall cohort of men starting treatment with abiraterone or enzalutamide (N = 202), according to CTC status and AR-V7 status. (A) Waterfall plots depicting best PSA responses according to CTC status and AR-V7 status, expressed in three categories: CTC–, CTC+/AR-V7–, and CTC+/AR-V7+. The dotted line illustrates the threshold for defining a PSA response (≥ 50% PSA reduction from baseline). PSA response rates in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients were 75.5% (40 of 53), 52.2% (59 of 113), and 13.9% (5 of 36), respectively (P < .001). All three groups were significantly different from each other (CTC– v CTC+/AR-V7–, P = .005; CTC– v CTC+/AR-V7+, P < .001; CTC+/AR-V7– v CTC+/AR-V7+, P < .001). (B) Kaplan-Meier curves indicating PSA progression-free survival according to CTC status and AR-V7 status. Median PSA progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 11.3 months (95% CI, 8.7 to 13.8), 6.2 months (95% CI, 5.8 to 7.3), and 2.1 months (95% CI, 1.9 to 3.1), respectively (P < .001). (C) Kaplan-Meier curves indicating clinical and radiographic progression-free survival according to CTC status and AR-V7 status. Median progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 13.9 months (95% CI, 11.0 to not reached), 7.7 months (95% CI, 6.2 to 10.1), and 3.1 months (95% CI, 2.3 to 3.7), respectively (P < .001). (D) Kaplan-Meier curves indicating overall survival according to CTC status and AR-V7 status. Median overall survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 28.7 months (95% CI, 28.4 to not reached), 29.5 months (95% CI, 18.4 to not reached), and 11.2 months (95% CI, 8.3 to 17.1), respectively (P < .001). AR-V7, androgen receptor splice variant-7; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig 2.

Clinical outcomes for men starting abiraterone or enzalutamide in the first-line novel hormonal therapy setting (N = 124), according to CTC status and AR-V7 status. (A) Waterfall plots depicting best PSA responses according to CTC status and AR-V7 status, expressed in three categories: CTC–, CTC+/AR-V7–, and CTC+/AR-V7+. The dotted line illustrates the threshold for defining a PSA response (≥ 50% PSA reduction from baseline). PSA response rates in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients were 86.1% (31 of 36), 65.8% (48 of 73), and 26.7% (4 of 15), respectively (P < .001). All three groups were significantly different from each other (CTC– v CTC+/AR-V7–, P = .03; CTC– v CTC+/AR-V7+, P < .001; CTC+/AR-V7– v CTC+/AR-V7+, P = .009). (B) Kaplan-Meier curves indicating PSA progression-free survival according to CTC status and AR-V7 status. Median PSA progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 12.7 months (95% CI, 11.7 to 23.9), 7.3 months (95% CI, 6.2 to 12.0), and 2.9 months (95% CI, 2.0 to not reached), respectively (P < .001). (C) Kaplan-Meier curves indicating clinical and radiographic progression-free survival according to CTC status and AR-V7 status. Median progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 21.6 months (95% CI, 13.9 to not reached), 10.1 months (95% CI, 7.9 to 14.9), and 4.1 months (95% CI, 3.0 to not reached), respectively (P < .001). (D) Kaplan-Meier curves indicating overall survival according to CTC status and AR-V7 status. Median overall survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 29.7 months (95% CI, 28.7 to not reached), 30.7 months (95% CI, 29.5 to not reached), and 21.5 months (95% CI, 10.4 to not reached), respectively (P = .003). AR-V7, androgen receptor splice variant-7; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig 3.

Clinical outcomes for men starting abiraterone or enzalutamide in the second-line novel hormonal therapy setting (N = 78), according to CTC status and AR-V7 status. (A) Waterfall plots depicting best PSA responses according to CTC status and AR-V7 status, expressed in three categories: CTC–, CTC+/AR-V7–, and CTC+/AR-V7+. The dotted line illustrates the threshold for defining a PSA response (≥ 50% PSA reduction from baseline). PSA response rates in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients were 52.9% (nine of 17), 27.5% (11 of 40), and 4.8% (one of 21), respectively (P = .003). All three groups were significantly different from each other (CTC– vs CTC+/AR-V7–, P = .078; CTC– vs CTC+/AR-V7+, P = .002; CTC+/AR-V7– vs CTC+/AR-V7+, P = .044). (B) Kaplan-Meier curves indicating PSA progression-free survival according to CTC status and AR-V7 status. Median PSA progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 6.4 months (95% CI, 5.1 to not reached), 4.4 months (95% CI, 3.2 to 6.0), and 1.1 months (95% CI, 1.0 to 3.1), respectively (P < .001). (C) Kaplan-Meier curves indicating clinical and radiographic progression-free survival according to CTC status and AR-V7 status. Median progression-free survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 6.2 months (95% CI 5.4–not reached), 5.3 months (95% CI 4.1–7.7), and 2.8 months (95% CI 2.1–3.4), respectively (P < .001). (D) Kaplan-Meier curves indicating overall survival according to CTC status and AR-V7 status. Median overall survival in CTC– patients, CTC+/AR-V7– patients, and CTC+/AR-V7+ patients was 18.8 months (95% CI 12.5–not reached), 13.0 months (95% CI 10.0–22.6), and 8.5 months (95% CI 4.9–15.6), respectively (P < .001).