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Variant Gives Hints as to Which Drugs Will Work in Prostate Cancer Patients

Susman, Ed

doi: 10.1097/01.COT.0000462860.60219.35
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A common androgen receptor variant found among metastatic castration-resistant prostate cancer patients could inform doctors what drugs they don't want to use in a subset of these patients, researchers reported at the Genitourinary Cancers Symposium (Abstract 138). The meeting is co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Scientists at Johns Hopkins University have identified what they believe is a biomarker that should rule out the use of androgen receptor-directed treatment—such as therapy with enzalutamide and abiraterone—in this group of patients who harbor the androgen receptor-splice variant 7 (AR-V7).

If a patient is found to have this variant in circulating tumor cells, it's likely that enzalutamide and abiraterone will have little effect, said Emmanuel Antonarakis, MD, Assistant Professor of Urology and Oncology at Sidney Kimmel Cancer Center at Johns Hopkins University.

The reason is straightforward, Antonarakis said in a news conference in advance of the meeting. “AR-V7 is a truncated form of the androgen receptor that is missing the ligand-binding domain, the target of enzalutamide and abiraterone,” he said. In other words, the area that enzalutamide and abiraterone require to perform their anti-cancer job isn't there in their patients.

Previously research by his team, reported at the most recent ASCO Annual Meeting, found that patients who harbor AR-V7 in their circulating tumor cells show evidence of primary resistance to both enzalutamide and abiraterone. In the new study, he explained, he and his colleagues sought to determine how well patients who have AR-V7-positive cancer would respond to treatment with taxanes (such as docetaxel and cabazitaxel).

What their preliminary experiments show, he said, is that patients with AR-V7-positive cancer and patients with AR-V7-negative cancer—i.e., patients with full-length androgen receptor status—respond similarly to taxanes for metastatic castration-resistant prostate cancer.

“I know validation tests of this biomarker are underway,” said Charles Ryan, MD, the moderator of the news conference and the designated ASCO expert and a member of the news planning team. He asked Antonarakis if the test was being routinely used by his group or by other groups.

That's sort of a problem, Antonarakis acknowledged. “As of now there is no CLIA-certified test for AR-V7. We are working on CLIA-certifying our assay at Johns Hopkins, but there is no commercially available assay for this at the present time. There are a number of biomarker companies that are working on this.”

When that test is available, and if other studies replicate the early work done by the Johns Hopkins team, he said, “In my mind, the utility of the test is greater in patients who have a positive result, and in those patients, I believe that our data suggest that taxanes might appear to be quite a bit more efficacious than either enzalutamide or abiraterone. However in the AR-V7-negative patients, it does seem like the drugs will be equally efficacious.”

In the work he presented at the symposium, Antonarakis and colleagues prospectively enrolled 37 men with metastatic castration-resistant prostate cancer who were about to start chemotherapy with either docetaxel or cabazitaxel.

“Patients had to consent to a peripheral blood draw for circulating tumor cells' collection and analysis using our assay to detect AR-V7,” he said. “We then tried to seek associations between the presence or absence of AR-V7 prior to chemotherapy initiation with a number of clinical outcomes.”

The primary outcome of the study was the prostate-specific antigen (PSA) response rate, defined as a 50 percent PSA reduction from baseline. Out of the 37 patients, 17 were positive for AR-V7 in their circulating tumor cells. “This is about 46 percent of the total population in this study,” Antonarakis noted, indicating that the variant occurs frequently in patients with metastatic castration-resistant prostate cancer.

EMMANUEL ANTONARAKIS, MD

EMMANUEL ANTONARAKIS, MD

Responses to taxanes occurred in both AR-V7-positive and -negative patients, he reported. In the patients who were harboring the variant, seven (41%) showed a PSA response to taxane therapy. Of the 20 patients who were not carrying AR-V7, 13 (65%) responded.

To further analyze the impact of AR-V7, the researchers incorporated data from another 62 patients who had been treated in the setting of enzalutamide and abiraterone to determine if the biomarker acted differently in the setting of taxanes than in the setting of androgen receptor directed therapy using enzalutamide and abiraterone.

“What we observed is that if a patient is AR-V7-positive in their circulating tumor cells, they have a greater chance of clinical or radiographic progression with enzalutamide or abiraterone compared with a taxane. The hazard ratio is 0.21, meaning that if a patient is AR-V7-positive, the chance of progression on a taxane is approximately 79 percent lower than if they received androgen receptor-directed therapy. Alternatively you can view this as a 4.8-fold increased risk of progression for AR-V7-positive patients who receive abiraterone or enzalutamide.”

On the other hand, it appeared that in patients who did not harbor AR-V7, “there does not appear to be a big difference in progression-free survival between the two therapies—the taxanes or abiraterone and enzalutamide,” he said. “In those patients who are AR-V7-negative, both therapies appear comparable.

“We would argue that detection of AR-V7 from circulating tumor cells in men with metastatic castration resistant prostate cancer is not associated with primary resistance to taxane therapy. AR-V7 positive patients do appear to retain some sensitivity to taxanes, and in this particular study there was a 41 percent PSA response rates to taxanes if the men were AR-V7 positive compared with zero percent to enzalutamide or abiraterone in this setting.

“In the AR-V7-positive setting, it is possible that taxanes might be more efficacious than androgen receptor-directed therapy,” he continued. “Therefore AR-V7 may potentially serve as a treatment selection marker for men with metastatic castration-resistant prostate cancer seeking therapy with either taxanes or enzalutamide or abiraterone. However, before these data become clinically actionable we need to prospectively validate this finding in at least one multicenter clinical trial.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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