PerspectiveIn the Journals

Men with AR-V7 variant may benefit from taxanes for advanced prostate cancer

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July 6, 2015

Men with advanced prostate cancer who have the androgen receptor splice variant-7 respond to chemotherapy equally as well as those who do not have the variant, according to findings from a small clinical trial.

Further, taxane chemotherapy may be more effective than hormone therapy for men with the androgen receptor splice variant-7 (AR-V7).

"The key finding from this study is that men with detectable AR-V7 in their circulating tumor cells may respond more favorably to chemotherapy (docetaxel or cabazitaxel [Jevtana, Sanofi]) compared to novel hormonal therapies (abiraterone and enzalutamide),” Emmanuel S. Antonarakis, MBBCh, assistant professor of oncology and assistant professor of urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, told HemOnc Today. “This finding was quite a relief because AR-V7–positive prostate cancer can be very lethal, and now we have at least one class of drugs that may work for these patients.” 

Emmanuel S. Antonarakis, MBBCh

Emmanuel S. Antonarakis

Antonarakis and colleagues previously demonstrated men with AR-V7 are resistant to hormonal drugs used in the treatment of prostate cancer — such as abiraterone (Zytiga, Janssen) and enzalutamide (Xtandi, Astellas) — which are androgen receptor-directed therapies used for castration-resistant prostate cancer.

Those hormonal drugs block the functionality and production of male hormones; however, AR-V7 is a shortened protein, and unlike the full-length proteins, is not dependent on androgens or hormones that cause the resistance to these therapies, according to study background.

Antonarakis and colleagues conducted this study to prospectively evaluate the impact of AR-V7 in men with advanced prostate cancer undergoing taxane chemotherapy.

The researchers evaluated circulating tumor cells (CTCs) from 37 patients with advanced prostate cancer. Thirty patients received docetaxel and seven received cabazitaxel.

The median follow-up among all patients was 7.7 months (range, 0.7-19.0).

Seventeen patients (46%) had detectable AR-V7 at baseline. The prevalence of AR-V7 was influenced by prior treatment of hormonal therapy as seven of 14 patients (50%) who had previously received abiraterone or enzalutamide were AR-V7–positive and eight of 15 patients (53%) who received both drugs were AR-V7–positive.

Overall, researchers observed no difference between AR-V7–positive and AR-V7–negative patients with regard to decline in PSA levels (41% vs. 65%).

However, in the researchers’ previous clinical trial of 62 men with advanced prostate cancer, the 18 patients who were AR-V7–positive showed no reduction in PSA levels with hormonal therapies. The findings of these two trials taken together could mean the AR-V7 variant may be a useful biomarker in the future to improve treatment decision-making for patients with prostate cancer, according to the researchers.

“It would be very useful to know if such patients are AR-V7–positive,” Antonarakis said in a press release. “Because, if they were, a better step for them might be chemotherapy rather than the alternative androgen-receptor directed hormonal therapy.”

Median PFS was 5.1 months in AR-V7–positive men and 6.9 months in AR-V7–negative men treated with chemotherapy (HR = 2.8; 95% CI, 1.2-6.9). When researchers adjusted for previous enzalutamide or abiraterone use, AR-V7 status no longer predicted PFS (HR = 2.7; 95% CI, 0.8-8.8).

Median OS also was comparable among AR-V7–positive (9.2 months) and AR-V7–negative patients treated with chemotherapy (14.7 months; HR = 2.5; 95% CI, 0.8-8.1).

Among AR-V7–positive patients, those who received taxanes vs. enzalutamide or abiraterone demonstrated a greater rate of PSA response (41% vs. 0%; P ˂ .001) and longer PSA PFS (HR = 0.19; 95% CI, 0.07-0.52) and PFS (HR = 0.21; 95% CI, 0.07-0.59).

Seven of the patients who were AR-V7–positive at the start of their chemotherapy became AR-V7–negative during treatment.

The researchers admitted that any clinical significance of this conversion remains unknown, but they hypothesized that some of these patients could then become re-sensitized to hormonal therapies after chemotherapy.

“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,” said Jun Luo, PhD, an associate professor of urology at the Johns Hopkins University James Buchanan Brady Urological Institute who discovered the AR-V7 gene variant in 2008, said in a press release. “But it’s something we should test in further studies.”

Antonarakis told HemOnc Today two other trials are addressing this question.

First, the researchers are looking to validate their findings in a prospective, randomized trial known as the PRIMCAB study.

“In this trial, men with primary resistance to abiraterone or enzalutamide will be randomized to receive either the alternative hormonal therapy (enzalutamide or abiraterone) vs. cabazitaxel chemotherapy,” Antonarakis said. “Patients will prospectively provide blood samples for AR-V7 analysis on this trial.”

If the findings are validated, there could be a cost benefit to this population as well since the hormone-based therapies are more than double the cost of chemotherapy, the researchers noted.

Secondly, the presence of AR-V7 is also being used as a selection marker for enrollment in the ARMOR3-SV trial.

“This is a phase 3 randomized study in which AR-V7–positive patients will be randomized to receive either enzalutamide or galeterone [TOK-001, Tokai Pharmaceuticals], a novel hormonal therapy that may be capable of degrading AR-V7,” Antonarakis said. “Additional drugs with activity against AR-V7 are also being developed, such as EPI-506 [ESSA Pharma], an androgen receptor inhibitor that blocks the N-terminal domain of AR which is preserved in all splice variants including AR-V7.” – by Anthony SanFilippo

For more information:

Emmanuel Stylianos Antonarakis, MBBCh, can be reached at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 401 N. Broadway, Baltimore, MD 21231; email: eantona1@jhmi.edu

Disclosure: Antonarakis reports consultant/advisory roles with Astellas, Dendreon, Essa, Janssen, Medivation and Sanofi; research funding from Dendreon, Exelixis, Genentech, Janssen, Johnson & Johnson, Novartis, Sanofi and Tokai; and is a co-inventor of a technology licensed to Tokai. See the full study for a complete list of all other researchers’ relevant financial disclosures. 

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PERSPECTIVE
Terence Friedlander

Terence Friedlander

In recent years, multiple new therapies have become available for men with metastatic castration-resistant prostate cancer. The hormonal therapies abiraterone acetate (Zytiga, Janssen) and enzalutamide (Xtandi; Astellas, Medivation) both target the androgen receptor (AR) in cancer cells and block androgen-mediated signaling, whereas the taxane chemotherapies docetaxel and cabazitaxel (Jevtana, Sanofi-Aventis) impair microtubule dynamics. While all of these agents can decrease PSA and prolong survival, each have different side effects, and a major challenge facing clinicians today is how to choose the appropriate agent for a given patient.

Recent evidence is shedding new light on this problem. Specifically, it has been long known that tumor cells adapt to androgen deprivation therapy through genetic changes that develop for the cancer cell to maintain AR signaling. A specific change in the processing of the AR protein, called a splice-variation, eliminates the portion of the AR protein that binds to androgens, but allows the receptor to constitutively bind to the cell’s DNA and promote growth and survival. In a prior study published in The New England Journal of Medicine, detection of a specific AR splice-variant — termed AR-V7 — in circulating tumor cells (CTCs) taken from men with metastatic castration-resistant prostate cancer, was shown to be highly predictive of response to the hormonal agents abiraterone and enzalutamide. In this study, Antanorakis and colleagues showed that men harboring detectable levels of AR-V7 in CTCs had no PSA responses to abiraterone or enzalutamide, and that these men had shorter PFS and OS compared with men who did not have detectable levels of AR-V7.

This intriguing finding suggests that men who have CTCs harboring detectable levels of AR-V7 fare worse with hormonal therapy compared with men who do not have detectable AR-V7. A major question that arose however, was whether AR-V7 is a marker that predicts response specifically to hormonal therapy, or whether AR-V7 is instead simply a marker of aggressive disease and overall poor prognosis.

To answer this question, the authors recently conducted a study published in JAMA Oncology in which the association of AR-V7 and response to taxane chemotherapy was investigated. Here, the authors collected CTCs and looked for the presence of AR-V7 at the outset of chemotherapy and then explored patients response to treatment. The authors found that although just under half of the 37 patients enrolled had detectable levels of AR-V7, the presence of AR-V7 did not predict response to taxane chemotherapy, with PSA responses observed in both groups and comparable PFS between the groups. As expected, patients whose tumors harbored AR-V7 appeared to have better outcomes with chemotherapy compared with androgen therapy, whereas patients who did not have AR-V7 appeared to benefit from either androgen therapy or chemotherapy.

What to make of these findings? Overall, these results lend support to the idea that the presence of AR-V7 is a biomarker that may specifically predict response to hormonal therapy for men with advanced disease, and is not simply a marker of poor prognosis. The fact that the authors are able to detect this in CTCs — as opposed to using a potentially painful and costly tissue biopsy — is exciting as this non-invasive test may be more suitable for patients, physicians and insurers than tissue biopsies. Perhaps more importantly, if confirmed in larger, multi-institutional studies using reproducible and certified assays, this work has the potential to allow clinicians to avoid giving ineffective treatments and better personalize therapy for patients with advanced prostate cancer.


Terence Friedlander, MD
USCF Medical Center

Disclosure: Friedlander reports no relevant financial disclosures.