Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer

Abstract

Background: Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used.

Objective: To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane.

Design, setting, and participants: The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3 yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes.

Outcome measurements and statistical analyses: We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status.

Results and limitations: Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; p =0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; p = 0.041). AR-V7-negative patients had superior survival on ARSIs over taxanes (p = 0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7-positive men.

Conclusions: Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures.

Patient summary: Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.

Keywords: AR-V7; Circulating tumor cells; Liquid biopsy; Prostate cancer; Treatment decisions.

Fig. 1 –

CONSORT and treatment diagrams. (A) CONSORT diagram outlining samples used for propensity score and risk score generation and subset analyzed. (B) Flow diagram illustrating cohort treatment and AR-V7 testing history. The scoring criteria for AR-V7 positivity were prespecified, and the AR-V7 results were not released to physicians. (C) Images of the presence or absence of nuclear-localized AR-V7 protein in circulating tumor cells (CTCs). ARSI = androgen receptor signaling inhibitor; PCWG = Prostate Cancer Clinical Trials Working Group.

Fig. 2 –

Factors influencing physician decisions to assign an androgen receptor signaling inhibitor (ARSI) or taxane. (A) Factors influencing physician decision to assign ARSI or taxane. Arrows indicate the relative odds for taxane use predicted by the model given the condition. (B) Distribution of patients by their propensity scores and actual therapy assigned, colored by AR-V7 status. Patients with a wide range of propensity to receive either an ARSI or a taxane could test positive for AR-V7. LLN = lower limit of normal; Tx = treatment; ULN = upper limit of normal.

Fig 3 –

Effect of therapy and AR-V7 status on overall survival. (A) Overall survival by drug class assigned; physicians were more likely to assign a taxane if the patient’s disease was more advanced. (B) Overall survival by drug class after weighting to adjust for physician propensity to administer either drug class influenced by pretherapy patient features, estimating drug-specific survival if cohort was randomized. (C) Overall survival by drug class and AR-V7 status in the context of (B). (D) Interaction multivariable Cox model for (C). ARSI = androgen receptor signaling inhibitor; CI = confidence interval; HR = hazard ratio; Tx = treatment.