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Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
J Clin Oncol 32:5s, 2014 (suppl; abstr 5001)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor that lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with mCRPC may be associated with primary resistance to enzalutamide and abiraterone. Methods: We used quantitative reverse-transcription PCR (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with mCRPC initiating treatment with enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA progression-free survival (PSA-PFS), and clinical/radiographic progression-free survival (PFS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on these clinical outcomes. 30 men (per cohort) were required to detect a difference in PSA response rates from 10% (in AR-V7–positive men) to 60% (in AR-V7–negative men), using a 2-sided α=0.10 and β=0.15. Results: 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median 1.4 vs 5.9 months, P<0.001), and PFS (median 2.1 vs 6.1 months, P<0.001) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median 1.3 months vs not reached, P<0.001), and PFS (median 2.3 months vs not reached, P<0.001). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length AR expression levels. Conclusions: Detection of AR-V7 in CTCs from men with mCRPC is associated with resistance to enzalutamide and abiraterone. AR-V7 status may be used as a biomarker to predict resistance to AR-targeting agents, facilitate treatment selection, and fuel the development AR N-terminal domain inhibitors.
Abstracts by Emmanuel S. Antonarakis:
- Meeting: 2014 Genitourinary Cancers Symposium | Abstract No: 263
A pilot study of supraphysiologic testosterone (T) and oral etoposide (E) in men with castrate-resistant prostate cancer (CRPC).
Clinical activity of enzalutamide pre- and post-docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).
Presentations by Emmanuel S. Antonarakis:
Randomized phase II trial evaluating the optimal sequencing of sipuleucel-T and androgen-deprivation therapy (ADT) in patients (pts) with biochemically recurrent prostate cancer (BRPC).Session: General Poster Session A: Prostate Cancer (General Poster Session)
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.Session: Genitourinary Cancer (General Poster Session)
A noncomparative randomized phase II study of two dose levels of itraconazole in men with metastatic castration-resistant prostate cancer (mCRPC): A DOD/PCCTC trial.Session: Genitourinary (Prostate) Cancer (Poster Discussion Session)