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

Chicago, IL (UroToday.com) AR-V7, a splice variant of the full length androgen receptor (AR), has been demonstrated to be associated with enzalutamide and abiraterone (both androgen receptor axis targeting agents) resistance, as demonstrated by Antonarakis et al.1 It is not associated with docetaxel chemotherapy resistance, as chemotherapy does not target the AR axis. Yet, it is unclear if its presence in circulating tumor cells (CTC’s) taken from blood samples is a valid predictive biomarker of clinical efficacy in men with mCRPC receiving Abi and Enza or if it is just an indicator of aggressive disease and high tumor burden.

The authors of this study, including Dr. Antonarakis, conducted a prospective study to help address this question. This is a multicenter prospective study of circulating biomarkers in men with high-risk mCRPC, entitled PROPHECY. All patients are being initiated on abiraterone or enzalutamide for their high-risk mCRPC, which is now SOC. Blood samples for CTC assessment was taken at baseline and serially throughout the study. Once initiated on the treatment, the primary endpoint was association of baseline AR-V7 with radiographic/clinical progression free survival (PFS), using the Johns Hopkins modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear AR-V7 protein assay. Overall survival (OS) and PSA decline were key secondary endpoints.

They defined a positive for each assay as follows:

image 33

It should be noted the full study extends beyond this test alone. The full schema is below:

image 33b

Subset CTC and circulating biomarker profiling and CellSearch CTC enumeration will be reported later. This abstract focuses specifically on the CTC AR-V7 assays.

They enrolled 118 men with mCRPC starting Abi or Enza. They had to have at least 2 high-risk features, in order to enrich the population with patients more likely to have CTC’s. High-risk features included: anemia, elevated alk phos, elevated serum LDH, prior ARAT therapy, visceral metastases, clinically significant pain, CellSearch count >= 5, PSADT <= 3 months, and radiographic progression at entry.

Baseline characteristics of the patients are listed below:
Median age 73
82% white, 12% AA
58% had Gleason 8-10
Median number of high risk features: 6 (very high risk group)
52% had ≥5 Cellsearch CTCs.
Interesting, 36% had been previously exposed to either abiraterone (A) or enzalutamide (E)
19% had had prior docetaxel

Patients on the study were treated A (n = 56), E (n = 59) or both A/E (n = 3) – on a trial protocol. No significant difference in outcomes demonstrated based on therapy – which confirms the cross-resistance biology. Median follow-up 19.6 months.

In terms of association, AR-V7 detection by the JHU AR-V7 assay and the Epic AR-V7 assay were independently associated with worse/shorter PFS (trended towards significance for Epic assay, p = 0.08) and OS (both significant) after adjusting for CTC count and established clinical factors such as PSA, alkaline phosphatase level and hemoglobin. Median PFS was significant worse in ARV7(+) regardless of assay: 3.1 months vs. 6.0/7.3 months. Median OS was similarly worse in ARV7(+) patients regardless of assay: 8.4/11.5 months vs. 25.5 months.

Concordance between the two AR-V7 assays was 82%. Epic AR-V7 (+) men had more CTC phenotypic heterogeneity: 63% had Shannon Index > 1.5 vs 14% of AR-V7 (-) men; most CTCs in Epic AR-V7 (+) men were AR-V7 (-).

Another important finding – with treatment, CTC AR-V7 levels increased, regardless of assay. Even in men who were AR-V7(+), most of their CTCs were ARV7(-) prior to therapy, but the proportion that were ARV7(+) increased after therapy.

They did find genetic alterations of aggressive mCRPC in AR-V7 (+) and AR-V7 (-) men including gain of AR, MYCN, and MYC and loss of PTEN, TP53, and DNA repair enzymes in CTCs and ctDNA.

In this excellent prospective assessment, even using two separate assays, the authors were able to demonstrate that CTC measurement of ARV7 at baseline is a independent CTC-adjusted predictive biomarker of shorter PFS and worse OS with Abi or Enza treatment in men with mCRPC.

Take-home points:
1. Men with CTC AR-V7(+) have a very low probability of response to ARAT
2. However, lack of AR-V7 detection does not guarantee benefit

Presented by: Andrew J. Armstrong, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:
1. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.
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