FDA approves enzalutamide for metastatic castration-resistant prostate cancer

Issue: September 25, 2012

The FDA today approved enzalutamide for patients with metastatic castration-resistant prostate cancer that has spread or recurred, despite medical or surgical therapy to reduce testosterone.

Perspective from Donald L. Trump, MD, FACP

Approved for prostate cancer patients previously treated with docetaxel, enzalutamide (Xtandi, Medivation Inc.) was reviewed under the FDA’s priority review program.

“The need for additional treatment options for advanced prostate cancer continues to be important for patients,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research said in an FDA release. “Xtandi is the latest treatment for this disease to demonstrate its ability to extend a patient’s life.”

The FDA based its approval on a study of 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel. The study was defined to measure OS in men receiving enzalutamide compared with men receiving placebo. The median OS for patients receiving enzalutamide was 18.4 months vs. 13.6 months for the patients who received placebo.

The most commonly observed adverse effects in study participants assigned enzalutamide were weakness or fatigue; hematuria; spinal cord compression and cauda equina syndrome; tissue swelling; diarrhea; musculoskeletal pain; headache; respiratory infections; dizziness; difficulty sleeping; tingling sensations; anxiety; and elevated blood pressure.

Seizures were reported in approximately 1% of those patients who received enzalutamide, at which point therapy was discontinued.

Exclusion criteria for the study consisted of patients with a history of seizure, temporary decrease in blood to the brain during the previous 12 months, reported underlying brain injury with notable loss of consciousness, stroke, brain metastases and patients taking medications that could lower the seizure threshold. At present, the safety profile for enzalutamide is unknown in patients with these conditions.

Perspective

Donald L. Trump, MD, FACP

FDA approval of enzalutamide is another step in the recent substantial progress in defining new therapies for prostate cancer. It is of interest – and sobering – that enzalutamide and abiraterone are the first agents whose mechanisms of action are unique in modulating the influences of androgen on prostate cancer, since the approval of flutamide (non-steroidal antiandrogen) and goserelin (LHRH analogue) in 1989. Enzalutamide interacts with the androgen receptor, but its mechanisms of action are distinct from other androgen receptor interactive agents in that enzalutamide inhibits nuclear translocation of the androgen receptor, DNA binding, and coactivator recruitment.

As should be the case with any important discovery in basic, translational or clinical research, the approval of enzalutamide sets the stage for the study of this agent in situations other than prostate cancer progressive despite castration. The efficacy and toxicity of this agent needs to be compared to abiraterone in docetaxel-refractory patients and studied in less advanced situations and in combination with LHRH analogues and/or abiraterone, in order to determine the full spectrum of activity –and importantly, toxicity of ablation of androgen signaling in treating men with prostate cancer. As the cost of all the newly approved agents is very high, delineation of the most cost-effective approaches to their use are also important. Some of these studies are underway and one hopes these questions can be answered sooner rather than later.

Donald L. Trump, MD, FACP

HemOnc Today Editorial Board member

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