New Biomarker Signals Poor Response in Prostate Cancer

Fran Lowry

May 04, 2017

A new test can identify men with castration-resistant prostate cancer (CRPC) who are likely to have a poorer response to the targeted hormonal therapies abiraterone acetate (Zytiga, Janssen) and enzalutamide (Xtandi, Medivation/Astellas), say British researchers.

Many prostate cancers rely on the androgen receptor gene (AR) to grow, the authors explain. The new test finds tumors with multiple copies of AR.

The finding, from a study published online May 3 in the Annals of Oncology, suggests that performing a blood test to quantify the AR gene could yield results that would predict who will benefit from targeted prostate cancer treatments, and who will not.

"Abiraterone and enzalutamide are excellent treatments for advanced prostate cancer, and some men can take these drugs for years without seeing a return of their cancer," senior author Gerhardt Attard, MD, from the Institute of Cancer Research (ICR), London, and the Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom, said in a statement.

"But in other men, these drugs do not work well, and the disease rapidy returns," he added.

"Currently, there is no approved test to help doctors choose whether these are the best treatments for an individual. We have developed a robust test that can be used in the clinic to pick out which men with advanced prostate cancer are likely to respond to abiraterone and enzalutamide, and which men might need alternative treatments," Dr Attard said.

"Our method costs less than £50 ($65.00), is quick to provide results, and can be implemented in hospital laboratories across the NHS [National Health Service]. We are now looking to assess our test in prospective clinical trials and would hope it can become part of standard patient care," he said.

Dr Attard and his team analyzed plasma DNA samples from 265 men with advanced prostate cancer who were taking part in three clinical trials.

In the primary trial, which included 171 patients, they evaluated associations between plasma AR levels and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naive and 98 post-docetaxel patients with CRPC who were treated with enzalutamide or abiraterone.

Among these men, AR gain was observed in 10 (14%) chemotherapy-naive and 33 (34%) post-docetaxel patients and was associated with significantly worse OS.

These men were four times more likely to die during the course of the study than men without AR gain.

For chemotherapy-naive patients, the hazard ratio (HR) was 3.98; (95% confidence interval [CI], 1.74 - 9.10; P < .001).

The risk for death was similarly high for post-docetaxel patients (HR 3.81; 95% CI, 2.28 - 6.37; P < .001).

These findings were confirmed in a second cohort of 94 patients. In that group, 11 (12%) with AR gain had significantly worse OS (HR, 11.08; 95% CI, 2.16 - 56.95; P = .004).

Study Highlights Importance of Biomarkers

"This paper provides additional and important insight into CRPC responsivity to enzalutamide or abiraterone as a function of the molecular status of the cancer's androgen receptor and highlights the emerging importance of biomarkers in assessing clinical outcomes in patients so treated," Marc Garnick, MD, Gorman Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, told Medscape Medical News.

"Prior studies of splice variants led to the finding that the presence of AR-V7 [androgen receptor splice variant 7] conferred less responsivity to treatments with abiraterone or enzalutamide, and this molecular profiling is now expanded to other alterations of the androgen receptor," said Dr Garnick, who is also editor in chief of the Annual Report on Prostate Diseases, published by Harvard Medical School.

"While the number of patients with confirmed androgen receptor copy number gain are relatively small, and the follow-up relatively short in the current study, the trend that those patients with these findings fared less favorably, independently of prior exposure to chemotherapy, is an important addition," he said.

On the clinical front, daily therapeutic decisions regarding the optimal and sequential use of hormonal therapies and adding chemotherapy are a matter of debate, he explained. An emerging question concerns whether chemotherapy should be used up front in combination with different frontline hormonal therapies, or whether it should be used later in the course of men with advanced and metastatic prostate cancer.

"The finding that AR mutations were not found in chemotherapy-naive patients is of interest and should help inform some of these treatment decisions," Dr Garnick said.

"As the authors point out, the ability to examine AR copy number gain and other AR mutations should serve the clinical research community well, as these potentially important molecular biomarker parameters can now be investigationally incorporated into clinical study designs that should provide more precise and rational treatment choices," he said.

This work was funded by Prostate Cancer UK and Cancer Research UK and was supported by the NIHR Royal Marsden and the ICR Biomedical Research Center. The ICR developed abiraterone and has a commercial interest in this agent. Dr Attard is on the ICR list of rewards to inventors for abiraterone and has received honoraria, consulting fees, or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Ventana, ESSA Pharmaceuticals, and Sanofi-Aventis and grant support from Janssen, AstraZeneca, and Arno. Dr Garnick has disclosed no relevant financial relationships.

Ann Oncol. Published online May 2, 2017. Full text

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