Xtandi (Enzalutamide) Now Approved for Metastatic, Hormone-Refractory Prostate Cancer Before Chemotherapy.

Golf course hole overlooking southwest inter-coastal waterway at Boca Grande, Florida; BJ Gabrielsen photo

Golf course hole overlooking southwest inter-coastal waterway at Boca Grande, Florida; BJ Gabrielsen photo

The following is an important blog in three sections. It describes another approved therapeutic agent for men with metastatic, hormone-refractory prostate cancer. Also included are important discussions regarding the need for future clinical studies to maximize cancer remissions and overall survival.

In 2012, the Food and Drug Administration approved Xtandi® (enzalutamide) for men with metastatic, hormone-refractory prostate cancer who previously had undergone chemotherapy with taxotere (docetaxel®). This month, however, the FDA approved Xtandi® for use in the same patients before they had been treated with chemotherapy, thus creating one more option for men. Xtandi® is a second line hormonal therapy administered orally once daily which can suppress testosterone at three different sources giving many men an additional cancer response after initially failing hormone therapy. The November 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights contains a very informative article by Dr. Neal Shore summarizing the use and mechanism of action of Xtandi®. The reader is advised to see the 2012 link at this point.

The second article by Dr. Mark Scholz is a blog from the February 2014 meeting of genitourinary section of American Society of Clinical Oncology (ASCO). Dr. Scholz mentions that Xtandi® (also formerly known as MDV3100 during its developmental stage) has been shown to extend life in both cohorts of prostate cancer patients discussed above. For specific details of the PREVAIL study, see the linked blog. Xtandi® now joins Zytiga® (abiraterone acetate) and Provenge® as therapeutic options for men before administering chemotherapy with taxotere. The question is now raised as to the optimal way to sequence administration of these agents. Dr. Scholz makes an argument that Provenge® which works by stimulating the immune system, should be administered first. After Provenge®, it is specially noted that the anticancer effects of Xtandi® is reduced when administered after Zytiga® and vice versa. This progressively increasing cancer resistance is not surprising. No data is currently available on the effect of sequencing these therapies on overall survival. Comparative studies and studies involving combination therapies are in order.

The third portion of this post are two very informative videos from Dr. Charles “Snuffy” Myers wherein he discusses the PREVAIL study results and prostate cancer remissions in general.  In the first video, Dr. Myers notes the significant delay in radiological progression (e.g. bone, lymph node metastases) demonstrated by Xtandi® (11.2 months vs. 2.8 months for placebo).  This will enable Xtandi® to be recognized as a first choice option for therapy. However, in the PREVAIL study, the overall survival result was less dramatic; only 2.2 additional months for Xtandi®. Dr. Myers poses the question of how a therapeutic agent can delay metastases yet minimally affect survival time.  He notes it may take a long time to observe the effects of a drug if one is basing the effects on following PSA changes alone. The PSA can increase while the whole cancer is responding. Hence, one should not overly depend on PSA. Instead he proposes using alkaline phosphatase and the circulating tumor assay (CTC) as better markers. Insurance coverage is also discussed. One needs to have a complete remission in order to see significant survival effects. It is rare to observe remissions from a single agent. Studies involving combination therapies are needed. Dr. Myers suggests that studies involving sequential single agents may not be the best, but combination studies are needed to witness overall survival benefits. The second video mainly discusses the mechanism of action of Xtandi®, its safety profile and potential side effects. Dr. Myers notes that under 20% of patients receiving Xtandi® in the PREVAIL study went into complete remission. It is more safe and effective than casodex (liver damage). The major side effect is fatigue. Four-six weeks are needed to reach a therapeutic drug level and 2-3 months are required to see a clinical benefit. The unique mechanism of action of Xtandi® may also require changes in other drugs being taken by a patient.

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