Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Abstract

Importance: We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.

Objective: To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men.

Design, setting, and participants: We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men.

Main outcomes and measures: We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone).

Results: Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7-positive and AR-V7-negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7-positive men, whereas outcomes did not differ by treatment type in AR-V7-negative men. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).

Conclusions and relevance: Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell-based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

Figures

Figure 1. Clinical Outcomes in 37 Taxane-Treated Patients, According to Circulating Tumor Cell Androgen Receptor Splice Variant 7 (AR-V7) Status

A, Waterfall plot depicting best prostate-specific antigen (PSA) responses, according to AR-V7 status. The dotted line shows the threshold for defining a PSA response (≥50% PSA reduction from baseline). Among patients who achieved a PSA response, 35% (7 of 20 men) were AR-V7 positive, whereas in those patients without a PSA response, 59% (12 of 17 men) were AR-V7 positive. B, Kaplan-Meier curves showing PSA progression-free survival in 37 taxane-treated patients, according to AR-V7 status. C, Kaplan-Meier curves showing clinical and/or radiographic progression-free survival in taxane-treated patients, according to AR-V7 status. D, Kaplan-Meier curves showing overall survival in taxane-treated patients, according to AR-V7 status.

Figure 2. Interaction Between Androgen Receptor Splice Variant 7 (AR-V7) Status and Treatment Type, After Including Data From Enzalutamide- or Abiraterone-Treated Patients

Kaplan-Meier analysis in 37 taxane-treated patients and 62 enzalutamide- or abiraterone-treated patients, separated according to AR-V7 status. A, Prostate-specific antigen (PSA) progression-free survival. A positive interaction between AR-V7 status and treatment type was observed (adjusted P = .001). B, Clinical and/or radiographic progression-free survival. A positive interaction between AR-V7 status and treatment type was observed (adjusted P = .003). C, Kaplan-Meier analysis showing overall survival in taxane-treated patients and enzalutamide- or abiraterone-treated patients, according to AR-V7 status. A significant interaction between AR-V7 status and treatment type was not observed (adjusted P = .16).

Figure 3. Clinical Outcomes With Taxanes vs Androgen Receptor–Directed Therapies for Androgen Receptor Splice Variant 7 (AR-V7)–Positive and AR-V7–Negative Patients

Kaplan-Meier analyses comparing taxane-treated patients vs enzalutamide (enza)- or abiraterone (abi)-treated patients. A, Prostate-specific antigen progression-free survival, focusing only on AR-V7–positive men. B, Clinical and/or radiographic progression-free survival, focusing only on AR-V7–positive men. C, Overall survival, focusing only on AR-V7–positive men. D, Prostate-specific antigen progression-free survival, focusing only on AR-V7–negative men. E, Clinical and/or radiographic progression-free survival, focusing only on AR-V7–negative men. F, Overall survival, focusing only on AR-V7–negative men.