Approval of enzalutamide pre-chemo a ‘game changer’

The FDA’s approval of enzalutamide (XTANDI) to treat metastatic castration-resistant prostate cancer (CRPC) in the pre-chemotherapy setting is a potential game changer for both patients and treating physicians, especially urologists, according to one leader in the prostate cancer field. 

The therapeutic options for this patient population will likely extend beyond enzalutamide, another pointed out. 

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Enzalutamide, an oral, once-daily androgen receptor inhibitor, was originally approved in 2012 for use in patients with metastatic CRPC who previously received docetaxel (Taxotere). The new indication approves enzalutamide for use in men with metastatic CRPC who have not received chemotherapy.

The most recent approval follows a priority review of the supplemental new drug application that was based on results of the phase III PREVAIL trial. In that study, men receiving enzalutamide and gonadotropin-releasing hormone (GnRH) therapy exhibited a statistically significant improvement in both overall survival and delayed time to radiographic progression or death as compared to those on placebo and GnRH therapy.

Enzalutamide significantly reduced the risk of death by 29% compared with placebo (HR: 0.71; p<.0001) and significantly reduced the risk of radiographic progression or death by 83% compared with placebo (HR: 0.17; p<.0001). When compared to placebo, treatment with enzalutamide also delayed time to initiation of chemotherapy and time to a skeletal-related event.

“In the PREVAIL trial, the median time to initiating chemotherapy was delayed by 17 months with enzalutamide treatment as compared to placebo, so the result is a meaningful period of time during which men have their disease controlled without the need for chemotherapy,” said PREVAIL co-principal investigator Tomasz M. Beer, MD, of Oregon Health & Science University, Portland.

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Enzalutamide’s oral formulation and ease of administration make it ideal for urologists to prescribe, said J. Brantley Thrasher, MD, of the University of Kansas Medical Center, Kansas City.

“I don't think the landscape will differ much for the medical oncologists. They have been using the drug for some time now off-label,” said Dr. Thrasher, a Urology Times editorial consultant. “The urologists, however, might have a game changer in this drug. The mechanism of delivery and the fact that enzalutamide is very ‘Casodex-like’ would leave me to believe that the urologists will adopt this drug rather quickly.

“It is a great drug and our experience has been that it is very well tolerated. I think urologists should embrace the drug, its use, and learn as much about it as they can.”

The sequence of enzalutamide prior to chemotherapy will allow urologists to remain engaged in patient care, rather than turning over patients to medical oncologists, when they often don't see them again, he pointed out.

“The approval of enzalutamide for use prior to chemotherapy adds to our therapeutic options for mCRPC patients,” said Neal D. Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, SC. “Urologists have already embraced sipuleucel-T [Provenge], abiraterone acetate [ZYTIGA], and radium-223 [Xofigo]. Additional real-world safety and tolerability data as well as cost effectiveness comparison will be important for urologist decision making concerning abiraterone and enzalutamide.”

Dr. Shore, member of the Urology Times Clinical Practice Board, pointed out that the final COU-302 overall survival and long-term safety analysis for abiraterone in this same patient population will be presented later this month at the European Society of Medical Oncology congress in Madrid.

“Furthermore, there are now three phase III trials of androgen receptor signaling inhibitors for the M0CRPC population: enzalutamide, ARN-509, and ODM-201. Hence, the plethora of quality therapeutic options continues to improve the treatment for patients with advanced prostate cancer, further requiring clinician educational awareness and dedication to this patient population,” Dr. Shore said.

The safety profile for enzalutamide has been updated to reflect data from both the AFFIRM and PREVAIL phase III trials.

Seizure occurred in 0.9% of patients receiving the drug who previously received docetaxel and 0.1% of patients who were chemotherapy-naive.

The most common adverse reactions (≥10%) that occurred more commonly (≥2% over placebo) in the enzalutamide-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight loss, headache, hypertension, and dizziness/vertigo.

Dr. Shore is a consultant/adviser to Astellas, Algeta, Bayer, Ferring, Dendreon, Janssen, Medivation,  Millenium, Sanofi, and BNI, and an investigator for Progenics Pharmaceuticals.

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