ASCO 2018: PROPHECY - A Prospective Trial of Circulating Tumor Cell AR-V7 Detection in mCRPC with Abiraterone or Enzalutamide

Chicago, IL (UroToday.com) Enzalutamide and abiraterone improve progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer1,2. However, a small proportion of men have primary resistance to enzalutamide or abiraterone, and essentially all men develop secondary resistance3.

There are three broad categories of acquired resistance, as described by Watson et al4:
  1. Restored AR signaling
  2. AR Bypass signaling
  3. AR independence
In the category of restored AR signaling are the androgen splice site variants. These variants code for a truncated androgen receptor protein which lacks the C-terminal ligand binding domain. However, it retains the transactivating N-terminal domain, causing constitutive activation of target genes3. A number of splice site variants have been discovered but the most clinically investigated variant is AR-V7.
In the landmark paper prospectively demonstrating that AR-V7 positivity is associated with resistance to enzalutamide and abiraterone, AR-V7–positive patients had a 0% PSA response rate compared with 53% of AR-V7–negative patients. AR-V7 positive patients also had shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months), and overall survival (median, 5.5 months vs. not reached; P = 0.002)3.

Given these extreme differences in clinical outcomes, detection of AR-V7 may prove useful to oncologists treating patients with mCRPC. Dr. Andrew Armstrong presented the PROPHECY trial:

Prophecy

The PROPHECY trial compares two current assays: the EPIC AR-V7 Nuclear Protein CTC assay and the Hopkins AR-V7 Adnatest assay. 


Prophecy Multicenter

The two assays along with a Cellsearch CTC assay was run before treatment for 118 men with progressive metastatic CRPC who had two or more high-risk features. The assays were then run after progression on enzalutamide or abiraterone, and then once again after the patients had taxane therapy. 

The primary endpoint was the association of baseline AR-V7 with radiographic/clinical progression-free survival. Overall survival and RECIST responses were key secondary endpoints.  At baseline, these men had a median age of 73, 82% Caucasian, 71% with a Karnofsky score greater than 90%. All men had bone metastases, with 33% of men having more than 20 bone metastases. 

In term of overall survival, there was no difference observed for OS between men treated with abiraterone or enzalutamide. At baseline, 24% of patients had a positive AR-V7 using the Hopkins assay and 10% using the EPIC assay. At the time of progression, 44% of patients had a positive AR-V7 assay compared with 20% using the EPIC assay. Concordance was 82% between the two assays.

AR-V7 detection was strongly correlated with median overall survival for both assays. Median overall survival was 27.2 months for the AR-V7 negative arm compared with 10.8 months for the AR-V7 positive arm in the Hopkins assay and 20.3 months vs 8.4 months in the EPIC assay. 0% of AR-V7 positive patients in the EPIC assay had a 50% or more confirmed PSA response, compared with 11% in the Hopkins assay. 

In conclusion, both tests were strongly predictive of overall survival. Men with AR-V7 positivity have a very low chance of benefitting from abiraterone or enzalutamide and if a patient is progressing on either therapy with a positive test, it would be prudent to switch to an alternative therapy such as chemotherapy. The investigators have a rich data source and I suspect further studies will be illuminating the role of serial AR-V7 testing in patients who have had a treatment break from abiraterone or enzalutamide. 


Presented By: Andrew J. Armstrong, MD, Duke Cancer Institute, Durham, NC

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:
1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. The New England Journal of Medicine 2014;371:424-33.
2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England Journal of Medicine 2011;364:1995-2005.
3. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. New England Journal of Medicine 2014;371:1028-38.
4. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nature Reviews Cancer 2015;15:701.
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