CHICAGO, IL USA (UroToday.com) - Resistance to novel medications that interrupt androgen receptor-driven cellular activity in metastatic castrate-resistant prostate cancer (CRPC) is poorly understood.
Androgen receptor splice variants (AR-Vs) have been described as one mechanism of resistance to these treatments. These AR-Vs enable the androgen receptor to be constitutively activated, theoretically rendering them immune to interruption of the steroid synthesis pathway (mechanism of abiraterone) and testosterone receptor antagonists (mechanism of enzalutamide). Whether tumors with AR-Vs are resistant to these medications in practice is unknown. Dr. Emmanuel Antonarakis and his colleagues sought to evaluate whether AR-Vs may be a mechanism of resistance to enzalutamide and/or abiraterone.
There are at least 20 identified AR-Vs currently. The majority of these AR-Vs consist of the first 3 exons of the receptor, followed by a cryptic exon that encodes for a premature stop codon that creates a truncated androgen receptor. AR-V7 is an AR-V that has been identified in human clinical samples, and is the most abundant of the AR-Vs. It is constitutively active and is not inhibited by current androgen receptor antagonists like enzalutamide. It is present in CRPC, at levels at least 20 times higher than in hormone-sensitive prostate cancer. The investigators in this study focused on this AR-V for their study of resistance to abiraterone and/or enzalutamide.
The investigators completed a prospective biomarker study that evaluated AR-V7 among patients treated with enzalutamide or abiraterone. Each arm of the study enrolled more than 30 men with metastatic CRPC and evaluated circulating tumor cells (CTCs) at baseline, during response to enzalutamide or abiraterone, and at the time of resistance to enzalutamide or abiraterone. The primary endpoint in the study was PSA response rate, defined as ≥ 50% decline in PSA, and secondary endpoints were PSA progression-free survival (PFS), and PFS.
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"The main limitation of our study was that the AR-V7 assay was performed in a research laboratory at our institution, and the analytical validity of the assay has not been established. In order to use this test to make clinical decisions, we will need to run it in a CLIA-certified setting. “If our results are replicated by other institutions using a standardized AR-V7 assay, then presence of AR-V7 in patient blood samples would be expected to result in lack of benefit from abiraterone and enzalutamide, and such patients might fare better with non-AR-targeting modalities such as chemotherapies, immunotherapies or radiopharmaceutical drugs." Emmanuel Antonarakis |
In the enzalutamide cohort (31 patients), 38.7% of patients were AR-V7 positive. None of the AR-V7-positive patients achieved the primary endpoint of best PSA response ≥ 50%, whereas 52.6% of the AR-V7-negative patients did. Two thirds of these patients had received prior abiraterone, perhaps explaining the relatively high rate of AR-V7 positivity in the cohort. In terms of PSA PFS and PFS, men with AR-V7 positive tumors were more than 7 times more likely to have PSA progression and more than 8 times more likely to have clinical or radiographic progression.
In the abiraterone cohort (31 patients), 19.4% were AR-V7 positive. Approximately 13% had received prior enzalutamide. Again, none of the AR-V7-positive patients achieved the primary endpoint of best PSA response ≥ 50%, whereas 68 % of the AR-V7 negative patients did. AR-V7 positive patients were more than 16 times more likely to experience both PSA and clinical progression.
The investigators also evaluated whether patients’ AR-V7 status converted during the course of the study. None of the AR-V7-positive patients became negative during the study. Fourteen percent of the AR-V7-negative patients became positive during the study. Additionally, the prevalence of AR-V7 increased with exposure to additional medications in the study. The prevalence of AR-V7 in men who had not received abiraterone or enzalutamide was 11.6%, 25% among men who had received prior enzalutamide, 51.2% among men who had received prior abiraterone, and 66.7% among men who had received both.
Ultimately the investigators note that it is possible, and likely feasible, to detect the presence of AR-V7 in CTCs from men with CRPC. They postulate that detection of this possible biomarker may predict primary and acquired resistance to enzalutamide and abiraterone. If this assay is reliable and repeatable in clinical practice, this may be an effective and relatively simple way of predicting which patients will or will not respond to treatment with these medications. If these findings hold true within a larger population, use of an assay to detect the presence of AR-V7 may someday be incorporated into clinical practice and assist in directing treatment in this population.
Presented by Emmanuel S. Antonarakis, MD at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD USA
Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com
