NEW YORK (GenomeWeb) – Researchers from Johns Hopkins University presented new data this week supporting expression of AR-V7 — a truncated form of the androgen receptor — in circulating tumor cells as a potential marker to guide therapy choice in patients with metastatic castration-resistant prostate cancer.
The group's leader Emmanuel Antonarakis shared the research at this week's American Society of Clinical Oncology Genitourinary Cancers Symposium.
Antonarakis and his colleagues had found in previous research that men whose CTCs tested positive for AR-V7 were resistant to the hormone drugs enzalutamide and abiraterone.
In its more recent study, the group looked to see if the same was true for taxane chemotherapy drugs.
If AR-V7 status was associated with resistance to both classes of drugs, it would suggest that marker is a more general predictor of prognosis, and therefore less useful as a tool to guide therapeutic decisions, Antonarakis said during a press call discussing the results.
But, if AR-V7-positive patients treated with chemotherapy did just as well as those who were AR-V7-negative, it would potentially solidify the marker's utility in choosing either hormonal or chemotherapy treatment.
"If you have a biomarker that is strongly prognostic in the setting of one therapy but not in the setting of the other therapy, then that becomes extremely useful as a treatment selection marker," Antonarakis told GenomeWeb.
Indeed, this is what the team found. In a cohort of 37 men, the researchers discovered that treatment outcomes on taxane chemotherapy were largely similar for the 17 AR-V7-positive and the 20 AR-V7-negative subjects.
A 50 percent reduction in PSA was achieved in 41 percent of AR-V7-positive men and in 65 percent of AR-V7-negative men — a difference that is not statistically significant, the authors reported. Median progression-free survival on taxane therapy was also comparable in AR-V7-positive and AR-V7-negative men — 5.1 months and 6.9 months, respectively.
On their own, these results wouldn't seem to bode well for the marker in predicting which patients should receive chemo. But coupled with the team's earlier results in patients on the hormone therapies abiraterone and enzalutamide, the data indicate that AR-V7 could actually be useful in deciding whether a man with CRPC should receive chemotherapy or hormone therapy.
When the group combined its data on the 37 chemo-treated men with previously published results from their abiraterone or enzalutamide study, it found that men who were AR-V7 positive appeared to do significantly better on chemotherapy than on hormone therapy while those who were negative did about the same on either therapy.
The researchers calculated that "if a patient is AR-V7 positive, their chance of progression on a taxane is approximately 79 percent lower than on an AR-directed therapy," Antonarakis explained.
Or, in other words, there is a 4.8-fold greater risk of progression for AR-V7-positive patients who receive abiraterone or enzalutamide instead of taxane chemotherapy, according to the group's results, he said.
The evidence suggests that AR-V7-positive patients might benefit from being offered chemotherapy rather than hormone therapy as initial treatment for castration-resistant prostate cancer, while those who are AR-V7-negative could safely choose either regimen.
"In my mind the utility of the test is greater in patients who have positive results," Antonarakis said during the call. "I believe our data suggests that in those patients, taxanes appear to be quite a bit more efficacious than either abiraterone or enzalutamide."
He stressed that it will be important for additional data to be collected, ideally in a multi-center clinical trial, to further prospectively validate the team's findings.
Meanwhile, the Hopkins group is currently working on developing a CLIA-certified AR-V7 test that it can begin to use in clinical practice. Currently there is no commercially available clinical test for the marker.
In their research, the investigators have been using qRT-PCR to measure AR-V7 status in circulating tumor cells. Antonarakis said that the CLIA version of their assay will be largely identical to what they have previously published.
Briefly, the method involves CTC isolation and enrichment using the AdnaTest Prostate Cancer Select kit from AdnaGen, an Alere company, followed by the AdnaTest Prostate Cancer Detect with multiplexed qRT-PCR primers to detect the presence of CTCs. Then custom-designed primers are used to detect both full-length-AR and AR-V7. The relative AR-V7 transcript abundance is determined by calculating the ratio of AR-V7 to its full-length equivalent.
Antonarakis told GenomeWeb that he and his colleagues expect to have the test CLIA-certified within six months.
In parallel to the work discussed at this week's symposium, the Hopkins team has also been involved in a collaboration in which they have licensed IP related to AR-V7 testing to Tokai Pharmaceuticals, which is working with Qiagen to develop a non-invasive AR-V7-based companion diagnostic for its investigational CRPC drug galeterone.
Antonarakis said that the galeterone CDx work is proceeding separately at this point from his group's internal development atHopkinsof an AR-V7 assay to guide treatment with taxane chemotherapy versus hormone therapy.
The Qiagen/Tokai effort is also not the only one seeking to commercialize an AR-V7 assay. Antonarakis said that several biomarker companies are also developing their own AR-V7 tests, the most promising of which in his eyes is an assay being developed by Epic Sciences using its CTC platform.