Next-Generation Therapies in CRPC Take Aim at AR Resistance

Ariela Katz
Published: Wednesday, Apr 19, 2017
Robert Dreicer, MD, MS

Robert Dreicer, MD, MS

As a wealth of research has shown in the past several years, therapies that target the androgen receptor (AR) pathway in patients with castration-resistant prostate cancer (CRPC) encounter complex mechanisms of resistance including the likelihood that more than 1 such signaling network is active in each individual (Figure).

Figure. Androgen Receptor Targeting and Resistance in Prostate Cancer

Figure. Androgen Receptor Targeting and Resistance in Prostate Cancer

Such mechanisms of resistance include AR-V7 splice variants, glucocorticoid activation of AR, gain of function mutation in dihydrotestosterone (DHT), and progesterone-responsive mutant ARs, according Robert Dreicer, MD, MS, during a presentation at New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies that Physicians’ Education Resource® (PER®) hosted March 18 in New York City. Emerging antihormonal agents for treating patients with advanced CRPC are being developed to mitigate AR resistance.

Currently, initial management of a patient with metastatic CRPC involves assessing the duration of response to androgen deprivation treatment (ADT), and then the subsequent administration of AR-directed therapy. Clinicians often choose between the AR inhibitors abiraterone acetate (Zytiga) and enzalutamide (Xtandi), and monitor patients for response to the initial agent. However, 15% to 25% of patients experience a de novo resistance to AR inhibitors. There is also clinical evidence of cross resistance with abiraterone and enzalutamide, with crossover response rates of 15% to 30%.

According to Dreicer, head of the Medical Oncology Section and deputy director at the University of Virginia Cancer Center and co-director of the Paul Mellon Urologic Oncology Center, there is a “law of thirds” with these agents, whereby approximately one-third of patients will not respond, one-third will progress after 3 to 5 months, and one-third will have a more durable response. “Clinically, we learn things pretty early,” he said.

Dreicer explained that clinicians will start a patient on either AR inhibitor and, if the patient does not have a durable response, then they will usually switch to docetaxel followed by the other AR inhibitor option, despite the clinician’s doubts of efficacy.

Signals From AR-V7 Variants

AR-V7 splice variants have gained much attention in recent years. Immunohistochemistry staining has established their increased expression in patients with CRPC. It has been shown to regulate both AR-regulated genes and a unique set of genes independent from the AR, suggesting that it has an overlapping, yet distinct, role compared with full- length AR in prostate cancer cells.1

A paper published in The New England Journal of Medicine concluded that detection of AR-V7 in the circulating tumor cells of patients with CRPC may be associated with resistance to abiraterone and enzalutamide.2 In this study, 31 patients treated with enzalutamide and 31 patients treated with abiraterone were tested for AR-V7. Thirty-nine percent of the enzalutamide group and 19% of the abiraterone group had detectable AR-V7 in circulating tumor cells. For participants receiving enzalutamide or abiraterone, AR-V7–positive patients demonstrated lower prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) rates than AR-V7–negative patients. It was also found that the association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length AR.2

This attention on AR-V7 led to some missteps in researching targeted treatments for patients with this variation. One such misstep was the ARMOR3 trial (NCT02438007), which compared galeterone with enzalutamide in men with metastatic CRPC expressing AR-V7. The study was terminated because the trial’s independent data monitoring committee determined that the trial was unlikely to meet its primary endpoint of improved radio-graphic PFS.

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