Test Indicates Prostate Cancers Resistant to Abiraterone

Alexander M. Castellino, PhD

November 11, 2015

A blood test that identifies nonresponsiveness or resistance to a drug has obvious clinical utility, especially in the era of precision medicine, as more treatments have narrowed targets and big price tags.

Such a test may be in the offing for patients with metastatic castration-resistant prostate cancer (CRPC) who are candidates for treatment with abiraterone (Zytiga, Janssen Pharmaceuticals, Inc), according to a report published online November 4 in Science Translational Medicine.

In the report, researchers used "liquid biopsies" to identify amplifications in the androgen receptor (AR) gene that are associated with resistance to abiraterone, which is approved for the treatment of CRPC cancer.

"Currently, there is no way to identify patients who will not benefit from further hormonal therapy [eg, abiraterone, enzalutamide (Xtandi, Astellas Pharma, Inc)]. The blood test we've developed appears to predict whether a patient will not respond to abiraterone," senior author Gerhardt Attard, MD, PhD, clinician scientist at the Institute of Cancer Research, London, United Kingdom, told Medscape Medical News.

The new research was also undertaken by Italian scientists at the University of Trento and the Research Institute in Meldola.

"In addition, our test also identifies AR mutations emerging in a group of patients who develop resistance to abiraterone during treatment," Dr Attard said.

"The presence of genomic AR alterations, as detected from circulating tumor DNA [ctDNA], may prove to be a very useful predictive biomarker, and it adds to a larger narrative regarding what can be learned from a simple blood draw," Michael T. Schweizer, MD, of the University of Washington, in Seattle, told Medscape Medical News.

Dr Schweizer coauthored an accompanying focus article with Emmanuel S. Antonarakis, MD, of the Johns Hopkins School of Medicine, in Baltimore, Maryland.

Dr Schweizer was referring to work from Dr Antonarakis' group, which earlier reported that an alternative splicing form of AR mRNA (AR-V7) from circulating tumor cells (CTCs) also correlated with response to taxanes and resistance to abiraterone and enzalutamide.

Two experts not involved with this research were enthusiastic about the findings reported in the current study and about their significance for the clinical management of CRPC in the future.

"The ability to both identify alterations in circulating cell-free DNA and apply them to clinical interventions — without the need for invasive biopsies and their attendant adverse events and inconvenience — will again up the precision with which both treatment decisions and clinical research questions can be more precisely posed," Marc B. Garnick, MD, Gorman Brothers Professor of Medicine at Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"This was a biomarker discovery effort and has highly encouraging data that if validated as part of routine care may allow us to determine which patients with CRPC should get abiraterone or alternative therapies, such as chemotherapy," Christopher J. Sweeney, MBBS, medical oncologist at the Dana-Farber Cancer Institute, Boston, told Medscape Medical News.

Liquid Biopsies Link Abiraterone Nonresponsiveness to AR Gene Amplification

Researchers used advanced sequencing procedures (next-generation sequencing and digital droplet polymerase chain reaction) on ctDNA isolated from blood samples of 97 patients with CRPC who initiated therapy with abiraterone. Isolating ctDNA from blood samples — also called liquid biopsies— may preclude the need for tissue biopsy procedures, which is a more invasive procedure.

The authors defined a minimum amount of tumor DNA required in 4-mL blood samples for these assessments. Of 97 patients, sufficient tumor DNA, extracted from approximately 4 mL of blood per sample, was available from 80 patients for these studies. Blood samples were taken within 30 days of treatment initiation. Patients were provided the option of undergoing blood testing every 8 weeks on treatment with abiraterone and on progression.

Among other alterations, DNA isolated from blood samples was interrogated for a gain in AR gene copy number and for L702H or T828A AR point mutations. The goal of the study was to determine whether AR gene aberrations associated with ≥50% decline in prostate-specific antigen (PSA) levels — a test used to determine treatment failure.

Of these 80 patients, 32 tested positive for AR gene alterations prior to treatment with abiraterone. The researchers reported that patients whose results were positive on this test were five times less likely to have a ≥50% decline in PSA (P = .002) and were nearly eight times less likely to have a decline ≥90%.

AR gene alterations in these patients treated with abiraterone also corresponded with significantly worse clinical outcomes of overall survival (hazard ratio [HR], 7.33; 95% confidence intervals [CI], 3.51 - 15.34; P < .0001) and progression-free survival (HR, 3.73; 95% CI, 2.17 - 6.41; P < .0001).

Significance for Clinical Practice

In their focus article, Dr Schweizer and Dr Antonarakis provide insights into the role of AR genes in CRPC. "It has recently been recognized that AR-regulated target genes continue to be expressed despite ADT [androgen-deprivation therapy] and that the AR remains a key driver of CRPC," they write.

"Currently, with the approval of new drugs, the treatment options for CRPC have expanded significantly," Dr Attard told Medscape Medical News.

We often choose one therapy over another without any certainty. Dr Gerhardt Attard

"Approximately 50% to 60% of patients respond to one treatment modality but not another. Because of our inability to identify patients likely to respond, we often choose one therapy over another without any certainty as to which treatment is better. Moreover, it takes a while to confirm that a treatment is not working, usually about 3 to 6 months," he said. "Therefore, with sequential treatments, patients become quite sick and have a worsening quality of life, and additionally, there are cost implications," he added.

Dr Garnick agrees. "Tests such as these will help identify men most likely and least likely to respond to novel therapies, with the consequence being both better clinically and in cost- effectiveness," he said.

The observation that AR-V7 also predicts resistance to abiraterone and enzalutamide poses a conundrum as to whether to use CTCs or ctDNA from liquid biopsies to inform future clinical decisions.

Dr Schweizer and Dr Antonarakis agreed that circulating RNA–based assays are more problematic because RNA degrades more rapidly in plasma than tumor cells. "Another important limitation of CTC evaluation is that most platforms rely on a limited number of cell-surface antigens...to define what constitutes a tumor cell," they add.

"Analysis of ctDNA is likely to provide more information than just looking for AR-V7 in circulating tumor cells," Dr Sweeney told Medscape Medical News. "Dr Attard and colleagues were able to interrogate AR DNA mutations, and this can be expanded to analysis of mutations in other genes, such as PI3 kinase," he added.

Dr Attard indicated that the two tests — from CTCs and liquid biopsies — may identify the same or similar patients, owing to the similarity in results reported. "There is likely to be an overlap in patients using the two tests," he said.

"However, future studies will have to be designed to specifically ask this question, as we are currently unable to obtain good-quality transcript data from plasma. CTCs are required, and often the capture of sufficient cells typically occurs later in the disease," Dr Attard added.

Are We Ready for Clinical Practice?

How soon can liquid biopsies be used for clinical practice? Everyone — those interviewed and the study researchers and focus article authors — agreed that there is a need of prospective studies to determine whether biomarkers such as AR gene amplification or AR-V7 mRNA are sufficiently powerful to predict response or resistance.

"Each of these biomarkers provides slightly different information," Dr Schweizer told Medscape Medical News. "We do not know yet if one is better than the other," he added.

"A clinical trial involving up to 600 men has been proposed in which we aim to prospectively show that men who are positive with our test have significantly greater benefit from chemotherapy in preference to abiraterone or similar drugs," Dr Attard told Medscape Medical News. "We are waiting for appropriate funding to begin enrollment," he added.

"Chemotherapy has been used for the past 10 years; yet, in clinical practice, we tend to use it after hormone therapy, which is not appropriate therapy for up to 50% of men with CRPC who have primary resistance," he said.

Is the future for testing just around the corner? First, an assay needs to be developed that can be used in routine clinical laboratories, Dr Sweeney indicated.

Medscape Medical News asked Dr Attard about the availability of this test for clinical practice. "We are hopeful that companies that offer similar technologies will be interested in developing this assay for commercial use in prostate cancer," he indicated. However, Dr Schweizer indicated the need to be cautious before making these tests the standard of care.

But Dr Garnick told Medscape Medical News: "This is an important piece of molecular research, which will hopefully become mainstream in clinical practice in the not too distant future. The more widespread introduction and affordability of these technologies will be the next challenge that will hopefully be forthcoming in the not too distant future."

"[This study] represents an important first step in CRPC biomarker exploration. More work is needed, but with technology reaching a critical inflection point, the era of molecularly guided prostate cancer treatment is right around the corner," Dr Schweizer and Dr Antonarakis conclude in their focus article.

The Institute of Cancer Research, London, developed abiraterone and therefore has a commercial interest in this agent. Dr Schweizer reported no relevant financial relationships. Dr Antonarakis is a paid consultant to and has received funding from several industry sources; he is also the coinventor of a technology that has been licensed to Tokai. Several study authors, including Dr Attard, have reported receiving consulting fees from industry.

Sci Transl Med. Published online November 4, 2015. Article abstract, Focus article abstract


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