Despite the availability of hormonal therapy for the treatment of metastatic prostate cancer and the high response rates for these agents, most patients eventually experience progression to castration-resistant disease.

“Multidisciplinary team approaches have contributed to the enormous progress that has been made. They have led to well-designed clinical trials.  We now have new agents that substantially improve both quality of life and survival in patients with metastatic castration-resistant prostate cancer,” explained Cora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo Forlanini Hospital in Rome, during an Educational Session at the 2014 ASCO Annual Meeting.

Dr. Sternberg noted that patients are often treated with hormonal agents when they have biochemical failure (ie, a rise in prostate-specific antigen) with no clinical evidence of metastasis, and that these patients may also develop castration-resistant disease with metastases. Her lecture focused, however, on patients with metastatic castration-resistant prostate cancer and the new hormonal agents that have been studied before and after docetaxel—specifically, abiraterone (Zytiga), enzalutamide (Xtandi), and the investigational agent, orteronel.

“Castration-resistant prostate cancer remains driven by androgen receptor signaling from the beginning of its course until the end,” she noted. Both abiraterone and enzalutamide ultimately target the androgen receptor. Abiraterone decreases testosterone production from the adrenal glands, the testis, and the tumor cells themselves.  Enzalutamide interferes with androgen receptor signaling and has three different mechanism of action; enzalutamide is eight times more potent than bicalutamide in blocking the androgen receptor, she said. Both drugs are now U.S. Food and Drug Administration (FDA)-approved for metastatic castration-resistant prostate cancer that has progressed after docetaxel therapy.

Key Trials

The COU-AA-301 trial showed that abiraterone administered with prednisone twice daily improved median overall survival by 4.6 months, representing a 26% reduction in the risk of death.  Minimal toxicity was observed. This was the first study to show such impressive results in patients after having had docetaxel chemotherapy.

The AFFIRM trial showed that enzalutamide achieved a median survival benefit of 4.8 months, with a 37% reduction in risk of death. This drug has extremely good tolerability with few side effects. However, enzalutamide is associated with a ≤ 1% risk of seizures, and oncologists should not prescribe this drug in patients with a history of seizures. This is an area for further research, Dr. Sternberg said.

Both abiraterone and enzalutamide were also studied in the predocetaxel setting in men with metastatic castration-resistant prostate cancer in the COU-AA-302 and PREVAIL trials. “Results of both trials are quite remarkable,” Dr. Sternberg commented.

In COU-AA-302, abiraterone achieved a 57% reduction in the risk of progression and a 21% reduction in the risk of death, according to an interim analysis. Abiraterone gained FDA approval for treatment given before docetaxel based on the results of this trial.

The PREVAIL trial, also conducted in the predocetaxel setting, found that enzalutamide reduced the risk of radiographic progression by 81% and reduced the risk of death by 29%. The study was halted early by an independent data monitoring committee based on these results, and FDA approval is expected soon.

Orteronel, an androgen-lowering agent, has also been studied pre- and postdocetaxel. Although the ELM-PC 4 and ELM-PC 5 studies revealed an improvement in radiographic progression-free survival, the studies showed no improvement in overall survival. “The reason for this has to do with the fact that many drugs such as abiraterone and enzalutamide as well as docetaxel and cabazitaxel [Jevtana Kit] became available and were given to patients,” Dr. Sternberg noted.

Remaining Questions

Several questions remain on how best to use these new agents in metastatic castration-resistant prostate cancer, including optimal sequencing and combinations. Ongoing studies will look at these questions, including a study at The University of Texas MD Anderson Cancer Center that has combined abiraterone and enzalutamide; the phase III ALLIANCE trial, which randomly assigns patients 2:1 to enzalutamide vs enzalutamide plus abiraterone and prednisone; and the PLATO trial, in which all patients are treated with enzalutamide and, at progression, are randomly assigned to add-on abiraterone and prednisone vs abiraterone and prednisone plus placebo enzalutamide. ■

Disclosure: Dr. Sternberg has received research funding or honoraria from Astellas, Medivation, Janssen, and Millennium.