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.

Treatment sequence in castration-resistant prostate cancer: A retrospective study in the new anti-androgen era

“…In this setting, certain prior reports have indicated the possibility of the occurrence of cross-resistance when first-line chemotherapy with DOC was administered after the novel hormonal agent AA; by contrast, there have been few instances of DOC rechallenge following failure to respond to AA or other agents (15,16). The cross-resistance to AA and EZL, as well as EWS, has been attributed to the expression of an AR splice variant-7 (17,18). In conclusion, further prospective studies are required in order to determine the optimal treatment sequence in this new anti-androgen era.…”

Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer

“…In our current study, the baseline hemoglobin and ALP levels were significantly associated with the prognosis of OS. One of the potential pretreatment prognostic factors is the AR-V7 expression level in CTCs (12)(13)(14). Although the cohort studied was small, Antonarakis et al (13) reported that the AR-V7 expression level in CTCs was prognostic of the outcomes of CRPC treatment.…”

“…The AR-V7 mutant, which lacks the ligand-binding domain of AR, has attracted attention in terms of resistance to AR-targeting agents (12). AR-V7 expression by circulating tumor cells (CTCs) was significantly associated with resistance to enzalutamide and abiraterone acetate (13,14). However, no commercial method of detecting AR-V7 in CTCs is yet available.…”

Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion?

“…1 A recent study published in June 2015 in JAMA Oncology (Antonarakis et al) found that AR-V7 status had no negative effect on taxane efficacy. 2 In the previous study, AR-V7 positive and in AR-V7 negative patients treated with enzalutamide and abiraterone treatment resulted in 0% and 53% decreases (P D 0.004) in prostate-specific antigen (PSA), while in this study docetaxel or cabazitaxel treatment resulted in 41% and 65% decreases (P D 0.19) respectively. The sample size in both studies was small, and further validation of AR-V7 in drug efficacy must be demonstrated before its clinical use as a treatment biomarker.…”