Biomarker for Resistance to Enzalutamide in Prostate Cancer

Roxanne Nelson

April 10, 2014

SAN DIEGO — A new biomarker could help predict resistance to enzalutamide (Xtandi) in patients with prostate cancer, according to early data presented here at the American Association for Cancer Research 2014.

The biomarker is androgen-receptor splice variant-7 (AR-V7), a truncated form of the androgen-receptor protein that lacks the ligand-binding domain targeted by enzalutamide but remains constitutively active as a transcription factor, explained Emmanuel Antonarakis, MD, assistant professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

His team looked for AR-VT in the circulating tumor cells (CTCs) of patients with advanced prostate cancer, and reported results from 31 such patients. They found that those who had AR-V7 in their CTCs had a worse response to enzalutamide than those without detectable AR-V7.

Prostate-specific antigen (PSA) levels did not decline in any of the patients with detectable AR-V7; in fact, no patient with detectable AR-V7 achieved a PSA response.

In contrast, PSA levels dropped by at least 50% in 10 of the 19 AR-V7-negative patients after enzalutamide treatment.

Patients who tested positive for AR-V7 also had shorter progression-free survival than those who tested negative.

"AR-V7, the most important AR spliced variant, is present in circulating tumor cells in a significant subset of patients with metastatic castration-resistant prostate cancer," Dr. Antonarakis said at the meeting. "It is feasible to analyze AR-V7, as well as the full-length AR, from previously prospectively collected CTC samples, and detection of AR-V7 may be associated with resistance to enzalutamide."

Even though they are early, "we believe these data have immediate clinical implications," Dr. Antonarakis said.

"We suggest that patients with detectable AR-V7 in their CTCs be steered away from these AR targeting therapies, such as enzalutamide, and instead be offered options such as chemotherapy or radiation," he told attendees.

Too Soon for Bold Statements

However, at least one expert feels that it is too soon to make such a bold statement about steering patients who may have detectable AR-V7 in their CTCs away from enzalutamide. "Before we deprive a patient of an effective therapy, we really need more data on this," said M. Dror Michaelson, MD, PhD, clinical director of the Genitourinary Cancer Center at Massachusetts General Hospital in Boston.

Before we deprive a patient of an effective therapy, we really need more data.

For one thing, he told Medscape Medical New, there are many different technologies that are being used to extract CTCs. "There are no standards yet, and the technology is not available or accessible to everyone at this time," he said.

"The data are promising, but we are not there yet. We will need to establish some kind of standard for this," Dr. Michaelson explained. "As we develop more treatments for this population, it becomes increasingly important to tailor the therapy. But for right now, I would not deprive one of my patients of a potentially effective treatment based on this study."

Worse Progression-free Survival

Dr. Antonarakis and colleagues used quantitative reverse-transcription polymerase chain reaction analysis to examine CTCs for the presence or absence of AR-V7 in their cohort of 31 prospectively enrolled patients with metastatic castration-resistant prostate cancer who were beginning treatment with enzalutamide.

Of the 31 patients, 12 (38.7%) had detectable AR-V7 messenger RNA in their CTCs. PSA response rates were worse in people who were AR-V7-positive than in those who were negative (0.0% vs 52.6%; P = .004).

Median PSA progression-free survival was shorter in men who were positive for AR-V7 than those who were negative (1.4 vs 5.9 months; hazard ratio [HR], 7.4; log rank P < .001), as was median progression-free survival (2.1 vs 6.1 months; HR; 8.5; log rank P < .001).

On a multivariable Cox regression analysis, the presence of AR-V7 (HR, 3.5; P = .027), baseline PSA level (HR, 1.01; P = .042), and response to previous abiraterone (Zytiga) treatment (HR, 5.4; P = .039) were all independently predictive of PSA progression-free survival. The researchers also found that AR-V7 (HR, 3.7; P = .026) and previous abiraterone use (HR, 8.7; P = .049) were both independently predictive of progression-free survival.

This study was funded by the Prostate Cancer Foundation. Dr. Antonarakis has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2014. Abstract 2910. Presented April 7, 2014

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