CTC AR-V7 Validated as Predictive Marker of Resistance to AR-Directed Therapy in mCRPC

Andrew J. Armstrong, MD

Nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells (CTCs) is a predictive marker of shorter progression-free and overall survival (OS) with antiandrogen therapy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from the phase III PROPHECY trial that were published in the Journal of Clinical Oncology.¹

Results showed that AR-V7 in CTCs, according to 2 blood-based assays, is predictive of whether men with mCRPC have become resistant to androgen receptor (AR) inhibitors, such as enzalutamide (Xtandi) and abiraterone acetate (Zytiga), and have a low chance of benefiting from additional AR-driven therapy.

When evaluated with the Oncotype DX AR-V7 Nucleus Detect test and the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay, the median progression-free survival (PFS) for patients who were AR-V7 positive were shorter (HR, 2.4; 95% CI, 1.1-5.1; P = .020) and (HR, 1.9; 95% CI, 1.1-3.3; P = .032), respectively. Additionally, the OS through both assays were also associated with shorter OS outcomes (HR, 3.5; 95% CI, 1.6-8.1) and (HR, 4.2; 95% CI, 2.1-8.5), respectively, after adjusting for CTC number and clinical prognostic factors.

The findings suggest that AR-V7—positive patients with mCRPC should be treated with either taxane chemotherapy or enroll on a clinical trial with investigational therapy.

"In this study, we demonstrate in a prospective, blinded manner that men with high-risk metastatic castration-resistant prostate cancer who are AR-V7 positive have little evidence of clinical benefit from abiraterone or enzalutamide, with short duration of overall and progression-free survival,” said lead study author Andrew J. Armstrong, MD, ScM, FACP, professor of medicine, surgery, pharmacology and cancer biology, director of Research, Duke Cancer Institute Center for Prostate and Urologic Cancers, Divisions of Medical Oncology and Urology at Duke University, in a press release.2 “Epic Sciences' AR-V7 test may better inform the decision to pursue further [AR-signaling] therapy prior to starting second-line [AR-signaling] treatment, rather than using these agents for a few months and then stopping if the treatment is ineffective.”

In the prospective, multicenter, blinded, phase III PROPHECY trial, investigators sought to validate the predictive significance of baseline CTC AR-V7 in 118 patients with undergoing AR-directed therapy. The primary endpoint was validation of prognostic significance of baseline CRC AR-V7 through radiographic or clinical PFS; OS and prostate-specific antigen (PSA) responses were secondary endpoints.

The median age was 73 years (range, 45-92); most patients were white (82%) and more than half had a Gleason score sum of 8 to 10 (58%). Seventy-one percent of patients had a Karnofsky performance status ≥90, and the median number of high-risk features was 6.

Of the 118 enrolled patients, 55 received treatment with abiraterone and 58 patients received enzalutamide; 5 patients received both agents concurrently. At a median follow-up of 19.6 months, the median PFS in the overall population was 5.8 months (95% CI, 4.1-7.6) and the median OS was 20.3 months (95% CI, 17.0-27.2).

At baseline, via the John Hopkins mRNA assay, 24% of patients were AR-V7 positive and 75% were AR-negative; 2 patients were unevaluable. Via the Oncotype DX AR-V7 Nucleus Detect test, 9% of patients were AR-V7 positive and whereas 82% were AR-V7 negative; 9% of patients were unevaluable. Moreover, there was an 82% observed percentage agreement between the 2 assays.

"One of the unique aspects of this multicenter study was that laboratory investigators were blinded to the clinical results, and clinicians were blinded to the laboratory results, and that the definitions of a positive test for AR-V7 were defined in advance and thus prospectively validated,” said Armstrong in the press release. “Having a reliable test that is associated strongly with a lack of clinical benefits to a therapy can help a patient and doctor pick a more effective therapy and not waste valuable time, resources and unnecessary toxicities from an ineffective, cross-resistant drug. Such information can enable oncologists to identify potentially life-extending treatments for these men with aggressive disease."

Results also showed that patients with mCRPC who are AR-V7 positive had few confirmed PSA responses (0%-11%) or soft tissue responses (0%-6%).

When stratified by assay, the median PFS for AR-V7—positive patients versus AR-V7–negative patients were 3.1 months and 6.9 months, respectively (HR, 2.4; 95% CI, 1.5-3.7), with the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA test. Median OS was 10.8 months compared with 27.2 months for AR-V7–positive and –negative patients (HR, 3.9; 95% CI, 2.2-6.9), respectively.

With the Oncotype DX AR-V7 Nucleus Detect test, the median PFS was 3.1 and 6.1 months for AR-V7—positive and –negative patients, respectively (HR, 2.5; 95% CI, 1.3-4.7), and the median OS was 8.4 and 25.5 months, respectively (HR, 3.4; 95% CI, 1.6-7.0).

"Demonstration in the PROPHECY trial of our AR-V7 test's ability to predict which patients will not respond to a frequently utilized and important drug class is a tremendous achievement," said study coauthor Ryan Dittamore, chief of Medical Innovation at Epic Sciences. "This clinical evidence further supports the value of our liquid biopsy test in providing critical information for the clinical management of patients with advanced prostate cancer."

References

1. Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study [published online ahead of print: March 13, 2019]. J Clin Oncol. doi: 10.1200/JCO.18.01731.
2. Large Prospective Trial Validates Detection of AR-V7 Biomarker Using Epic Sciences' Platform to Predict Treatment Outcomes for Patients with Advanced Prostate Cancer. Epic Sciences. Published March 13, 2019. https://prn.to/2EXI9V0. Accessed March 13, 2019.