ASCO 2018-ASSAY PREDICT RESPONSE OF PROSTATE CANCER TO TREATMENT

Two circulating tumor cell (CTC) assays can predict which men with advanced prostate cancer are unlikely to benefit from anti-androgen therapies, researchers said in a June 4 presentation at ASCO 2018.

To determine whether androgen receptor splice variant-7 (AR-V7) in circulating prostate tumor cells is a valid predictor of clinical response to anti-androgen therapy or simply a marker of aggressive disease, researchers tested two assays: the CTC AR-V7 nuclear protein test (Epic Sciences/Genomic Health) and the CTC AR-V7 RNA test (Johns Hopkins University).

Neither assay has been approved by the US Food and Drug Administration.

For the validation study, Dr. Andrew Armstrong of the Duke Cancer Institute in Durham and colleagues enrolled 118 men with metastatic castration-resistant prostate cancer at five medical centers: 56 participants received abiraterone (A); 59, enzalutamide (E); and three, both.

AR-V7 detection by both assays was independently associated with worse progression-free and overall survival after adjusting for CTC count and established clinical factors.

Concordance between the two assays was 82%. Epic AR-V7-positive men had more CTC phenotypic heterogeneity: 63% had a Shannon Index greater than 1.5 versus 14% of AR-V7-negative men. Most CTCs in Epic AR-V7-positive men were AR-V7-negative, according to the authors.

Genetic alterations of aggressive mCRPC were found in AR-V7-positive and AR-V7-negative men, including gain of AR, MYCN and MYC genes, and loss of PTEN, TP53, and DNA repair enzymes in CTCs and ctDNA.

"We validate AR-V7 detection as an independent CTC-adjusted negative predictive biomarker of short progression-free and overall survival with A/E treatment in men with mCRPC, identify CTC heterogeneity of AR-V7 expression, and highlight the importance of non-AR-V7 drivers of aggressive disease," the authors state.

"The PROPHECY study included blood collections for multiple biomarkers beyond AR-V7, which will be the subject of future presentations and manuscripts," Dr. Armstrong told Reuters Health. "These include CTC enumeration (Cellsearch), ctDNA analysis, CTC DNA and RNA analysis, whole blood RNA panels including AR-V7 in cell free RNA, the Epic Shannon Index of CTC phenotypic heterogeneity, and the Cornell multiplex AR-variant assay."

"From this wealth of genomic and phenotypic data, we hope to be able to better identify AR-V7 negative men with mCRPC who are unlikely to benefit from abiraterone or enzalutamide," he said by email. "Conversely, we can use this data to identify men who are very likely to respond (i.e., extraordinary responders)."

Dr. Terry Friedlander, Associate Clinical Professor, Division of Hematology/Oncology at the University of California, San Francisco, said by email, "The study shows that overall, patients with this AR-V7 biomarker fare poorly when treated with the new AR-targeted therapies abiraterone or enzalutamide; however, the study does not address whether foregoing these AR-targeted treatments and starting an alternative approved therapy, such as chemotherapy, will actually benefit the patient. It is possible that these patients will do poorly regardless of treatment."

"That said," he told Reuters Health, "these patients should be prioritized for participation in clinical trials of novel therapies . . . and avoid losing time with ineffective therapies."

"A study in which patients who are AR-V7-positive are randomized to receive chemotherapy or AR-targeted therapy would address the question of whether the biomarker is mostly prognostic (poor outcome regardless of intervention) or predictive (poor outcome specifically to AR-targeted therapy)," he concluded.

Dr. Przemyslaw Twardowski, Director of Clinical Research in the Department of Urology and Urologic Oncology at John Wayne Cancer Institute in Santa Monica, California, told Reuters Health the findings "are well supported by data and essentially confirm in a more definitive way what was published previously."

"What would be helpful is confirmation that if a patient harbors the AR-V7 marker, the alternative therapy - like chemotherapy or other drugs - (would) perform better than abiraterone or enzalutamide," he noted. "This study confirms that AR-V7-expressing patients have poor prognosis, but how to treat them is an open question."

SOURCE: http://bit.ly/2M4k9lA

ASCO 2018.