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Chemotherapy May Be Preferred Option for Some With Advanced Prostate Cancer

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Key Points

  • Men with the AR-V7 variant are resistant to androgen receptor–directed therapies such as enzalutamide or abiraterone.
  • Seven of 17 (41%) AR-V7–positive patients in the study receiving chemotherapy achieved a 50% reduction in PSA levels.
  • AR-V7 variant could be used someday as a biomarker for patients with prostate cancer. The incidence of AR-V7 among these patients may be as high as 30 to 40%, said researchers.

In a small clinical trial, scientists at Johns Hopkins Kimmel Cancer Center and James Buchanan Brady Urological Institute found that men with advanced prostate cancer and detection of androgen receptor splice variant-7 (AR-V7) respond to chemotherapy just as well as men who lack the variant.

The findings, the researchers say, may be significant for patients who carry the AR-V7 variant, because they are more likely to develop resistance to one of two hormone drugs routinely used to treat the disease. Results of the trial were published by Antonarakis et al in JAMA Oncology.

AR-V7 and Drug Resistance

The AR-V7 gene variant was discovered in 2008 by James Buchanan Brady Urological Institute researcher Jun Luo, PhD. In a previous study, Dr. Luo and Emmanuel Antonarakis, MD, found that men with the AR-V7 variant were resistant to hormonal drugs, such as enzalutamide (Xtandi) or abiraterone (Zytiga), androgen receptor–directed therapies used for the treatment of castration-resistant prostate cancer.

Abiraterone and enzalutamide, said Dr. Antonarakis, aim to block the production and function of male hormones. The AR-V7 variant codes for shortened proteins that—unlike full-length AR proteins—regulate prostate cancer growth, which is not dependent on androgens. Therefore, men who have the AR-V7 variant are more likely to be resistant to hormone drugs.

In a previous clinical trial of 62 patients with castration-resistant prostate cancer, the same researchers found that 18 AR-V7positive patients who took either enzalutamide or abiraterone showed no reduction in their prostate-specific antigen (PSA) levels, indicating that the drugs were not effective in these patients.

Study Findings

In the new trial, including 37 men being treated with either docetaxel or cabazitaxel (Jevtana Kit) at The Johns Hopkins Hospital, 17 had detectable levels of the AR-V7 variant in their blood. In comparing men with and without the gene variant, there was no statistical difference in how much patients’ PSA levels declined, how long it took for their cancers to progress, or their overall survival. Seven of 17 (41%) AR-V7-positive patients receiving chemotherapy achieved a 50% reduction in PSA levels.

“Our study shows that men who have the AR-V7 gene variant and don't respond to either abiraterone or enzalutamide are not at a disadvantage when given chemotherapy drugs,” said Dr. Antonarakis, an oncologist at the Kimmel Cancer Center.

Taken together, Dr. Antonarakis said, the findings, if confirmed in larger trials, suggest that the presence of the AR-V7 variant could be used someday as a biomarker to improve treatment decision-making for patients with prostate cancer. The incidence of AR-V7 among these patients may be as high as 30% to 40%, he noted.

“We think AR-V7 would have the greatest utility as a biomarker to guide further treatment in men with castration-resistant prostate cancer, and not for earlier stages of the disease so far,” Dr. Luo said.

The researchers also detected what they say is an intriguing change among seven of the patients in the study who were AR-V7–positive at the start of their chemotherapy: During the course of that treatment, they converted to AR-V7negative. “The clinical significance of this is unknown, but one hypothesis is that some of these patients could possibly become resensitized to enzalutamide or abiraterone.”

There is no commercially available test yet for AR-V7, Dr. Antonarakis noted, which is detected in tumor cells circulating in a patient’s blood. But Dr. Luo and Dr. Antonarakis said that they are working to develop and validate an AR-V7 test that could be used more widely.

“The ultimate goal is to address needs of patients [for whom] standard therapy [fails],” said Dr. Luo. “By using the biomarker to improve patient-doctor decision-making, we could realize a therapeutic benefit without having to find a new drug.”

The researchers also noted that the two hormone therapies, abiraterone and enzalutamide, are considerably more expensive than chemotherapy. At more than $30,000 for a 6-month treatment, the hormone-based therapies are more than double the chemotherapy costs.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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