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Study Validates Oncotype DX AR-V7 Chemo Prediction

NEW YORK (GenomeWeb) – A newly published  multi-institutional cohort study has validated Epic Sciences' circulating tumor cell-based AR-V7 test, now marketed by Genomic Health as Oncotype DX AR-V7 Nucleus Detect.

The blinded study, published in JAMA Oncology, enrolled 142 patients with metastatic castration-resistant prostate cancer who were treated with either taxanes or androgen receptor signaling (ARS) inhibitors and observed for up to 4.3 years.

Examining patient outcomes alongside their pre-treatment CTC AR-V7 status, investigators concluded that individuals with AR-V7-positive circulating tumor cells had superior overall survival when treated with taxane chemotherapy versus androgen signaling inhibitors. Those who were AR-V7-negative at baseline, expectedly, had superior overall survival with hormonal treatment.

The effort was led by researchers from Memorial Sloan Kettering Cancer Center, Epic Sciences, The Institute of Cancer Research, UK, and London Health Sciences Centre, Canada, and is one of the first to validate that a liquid biopsy test can predict therapeutic response and demonstrate a survival benefit.

“During the treatment of metastatic prostate cancer, physicians will now be able to use AR-V7 status to determine when a patient’s cancer has become resistant to androgen receptor-directed therapy and will respond better to chemotherapy, enabling the patient to live longer," study PI Howard Scher, head of MSKCC's biomarker development initiative, said in a statement.

The test in question has now been available commercially for about four months through Genomic Health, and in March Medicare contractor Palmetto GBA issued a draft local coverage determination for the test, recommending limited coverage for its use to help determine which patients with metastatic castration-resistant prostate cancer may benefit from androgen receptor signaling inhibitor therapy and which may benefit from chemotherapy.

Prior research had already demonstrated that AR-V7 status is predictive of non-response to hormonal drugs. Earlier this month, for example, Andrew Armstrong of the Duke Cancer Institute presented data validating the Epic/Genomic Health test, as well as another test developed by researchers at Johns Hopkins, in a trial called PROPHECY.

But Epic has long sought to demonstrate prediction not only of a lack of hormonal therapy response, but also of better outcomes with chemotherapy treatment in AR-V7-positive men as a distinguishing factor for its test over others.

The company published a prior analysis in 2016, also in JAMA Oncology, which examined a cohort of 191 patients, and found higher PSA response rates, longer radiographic progression-free survival times, and better overall survival among AR-V7–positive men treated with taxanes relative to those who received ARS inhibitors.

The study's authors wrote that the new data represent a validation of those findings in an independent cohort, with clinical sites blinded to the biomarker result and the processing laboratory blinded to patient outcomes.

Investigators said that they have studied two patient populations in this way: those facing a choice of ARS inhibitors or taxanes after failed first-line treatment, and those in the first line. But the authors reported only on the second-line treatment cohort in their publication this week.

The results showed that men who were positive for AR-V7 via the Epic/Genomic Health test and were treated with taxane-based chemotherapy had a median overall survival of 14.3 months, while those treated with anti-androgen drugs survived only 7.3 months on average.

And in the reverse, patients who were AR-V7-negative survived much longer on average when treated with hormonal therapy than when given chemo — 19.8 months versus 12.8 months.

In a commentary accompanying the study, authors fromthe University of Washington and the Royal Marsden Hospital in London wrote that "if confirmed by prospective randomized studies generating level 1 evidence … a test that truly demonstrates futility of a specific treatment could be important, since treatment efficacy currently requires following prostate-specific antigen response for at least 4 weeks."

However, they added, there are still important unanswered questions that affect the potential clinical utility of AR-V7 testing. For one, there remain questions about false-negative rates using CTC-based assays, especially in first-line treatment, where many men, especially if they are chemotherapy-naive, may not have any CTCs in their blood.

In the PROPHECY trial data presented earlier this month at the American Society for Clinical Oncology annual meeting, both the Epic/Genomic Health test, and the Johns Hopkins-developed assay showed predictive ability. But they also identified different numbers of AR-V7-positive and -negative patients.

Since the JAMA study only assessed the Epic test, it doesn't add to evidence helping to clarify the nature of the discordances between these tests.

Authors of the commentary also argued that the data so far still don't establish that the Epic test is predictive versus just prognostic.

"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."

"We question whether the data reported herein support the use of this assay to select patients for treatment" with a second hormonal therapy versus a switch to chemotherapy," they concluded.

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