This article is more than 5 years old. Information may no longer be current.
Biomarker identifies men with prostate cancer who may benefit from chemotherapy
Click Here to Manage Email Alerts
A validated assay for detecting nuclear-localized androgen receptor splice variant 7 protein in circulating tumor cells identified men with prostate cancer who lived longer with taxane chemotherapy than with an androgen receptor signaling inhibitor, according to results of a multi-institutional cohort study.
“The test should be considered for patients for whom increased OS is an objective,” Howard I. Scher, MD, co-chair of the Center for Mechanism Based Therapy and head of the Biomarker Development Initiative at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “For patients with many comorbidities or who refuse a chemotherapeutic option, the androgen receptor splice variant 7 [AR-V7] test can still aid in patient management by identifying ARS inhibition-resistant disease for the purpose of directing patients to clinical trials or palliative care.”
Androgen receptor signaling (ARS) inhibitors and taxanes are widely used for progressive metastatic castration-resistant prostate cancer.
Although ARS inhibitors are preferred first-line treatment, prospective randomized clinical trial data comparing the agents directly has remained nonexistent. Further, no formal guidelines exist on how to sequence various ARS inhibitors to optimize individual patient outcomes, and a test that can better inform the choice of therapy in the second-line or higher setting has been a critical unmet need.
Researchers have identified resistance mechanisms to ARS inhibitors, including alterations in secondary signaling pathways and changes in the androgen receptor, such as amplification, mutations and splice variants with truncations in the ligand-binding domain, the most studied of which is AR-V7.
Scher and colleagues evaluated whether the nuclear-localized AR-V7 protein in circulating tumor cells could be used as a treatment selection marker for taxanes compared with ARS inhibitors.
Researchers developed a protein-based assay to identify AR-V7 circulating tumor cells using the Epic Sciences platform, a nonselection-based approach that deposits nucleated cells from a blood
sample onto pathologic test slides and uses fluorescent scanners to image each cell and identify circulating tumor cells.
Data from a training cohort of 191 patients’ blood samples evaluated prior to treatment with ARS inhibition or taxane therapy showed higher PSA response rates, longer radiographic PFS and improved OS among patients with nuclear-localized AR-V7-positive circulating tumor cells who received taxanes.
To validate these findings, researchers tested blood samples from 142 patients (mean age, 69.5 years) prior to treatment with taxanes (n = 72) or ARS inhibitors (n = 70) as second-line treatment or greater between December 2012 and September 2016.
Researchers noted ARS inhibitors were mostly used as second-line treatment, whereas taxanes tended to be used in later lines (proportion receiving taxanes as second line, 0.3; proportion receiving taxanes as third line or greater, 0.64; P < .001). However, researchers did not observe a difference between treatment choice based on median age, albumin levels, hemoglobin levels, or the presence of lung and/or liver metastases prior to therapy.
OS after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status served as the study’s primary endpoint.
Researchers considered 70 samples high risk based on conventional prognostic factors.
Among this group, patients positive for AR-V7 treated with taxanes had superior median OS than patients treated with ARS inhibitors (14.3 months vs. 7.3 months; HR = 0.62; 95% CI, 0.28-1.39). This may not have reached statistical significance due to the small sample size, according to the researchers.
Patients negative for AR-V7 had superior median OS when treated with ARS inhibitors than with taxanes (19.8 months vs. 12.8 months; HR = 1.67; 95% CI, 1-2.81).
“The study results validate the clinical utility of the Epic Sciences nuclear-localized AR-V7 assay to inform the choice between ARS inhibitors or taxanes for patients with metastatic castration-resistant prostate cancer who are in need of a treatment change in the second-line or greater therapy setting,” researchers wrote.
Still, there remains a need to determine whether the assay is prognostic or predictive, Stephen R. Plymate, MD, professor in the department of medicine at University of Washington, and colleagues, wrote in an accompanying editorial.
“Studies must correlate response to treatment with assay positivity, and not just survival data, to ensure that the assay is not simply a prognostic biomarker,” they wrote. “AR-V7 positivity, in this study, is associated with higher lactate dehydrogenase, alkaline phosphatase and prostate-specific antigen levels, suggesting a higher disease burden in the taxane arm. This finding indicates that
AR-V7 positivity by this assay may be more prognostic, associated with disease burden, than predictive.”
The evolving treatment landscape for castration-resistant prostate cancer makes the need for predictive biomarkers ever more urgent, they added.
“Earlier use of [newly approved] agents will result in increased earlier expression of AR splice variants, providing increased impetus for developing therapeutic strategies blocking AR splice variant signaling to improve outcomes. Predictive biomarker assays for these are needed,” Plymate and colleagues wrote. “We question whether the data reported herein support the use of this assay to select patients for treatment with enzalutamide [Xtandi; Astellas, Pfizer Oncology] after abiraterone [Zytiga, Janssen Oncology] or abiraterone after enzalutamide, especially since multiple groups have reported that that AR-V7-positive patients can still respond to these agents.” – by Melinda Stevens
Disclosures: Scher reports institutional financial support from Janssen and Medivation; personal fees from Astellas, Clovis and Sanofi Aventis; and research funding from Innocrin, Janssen Diagnostics and Janssen Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures. Plymate reports no relevant financial disclosures. Please see the editorial for all other authors’ relevant financial disclosures.
Click Here to Manage Email Alerts