Xtandi Gets Speedy FDA Ok For Metastatic Castration-Resistant Prostate Cancer

By Dr. Cheryl Strelko, GlobalData's analyst covering Oncology.

In an August 31, 2012 press release, Medivation, Inc. and Astellas Pharma, Inc. announced that their highly anticipated drug Xtandi (enzalutamide) has received an unusually speedy approval from the FDA for the treatment of metastatic castration-resistant prostate cancer (mCRPC) that has failed treatment with Sanofi’s Taxotere (docetaxel). After granting Xtandi priority review on July 23, 2012, the FDA had assigned a Prescription Drug User Fee Act (PDUFA) action date of November 22, 2012, but approved the drug a mere 39 days later. The drug was initially developed by Medivation, which later entered into a collaboration agreement with Astellas. Astellas will co-market Xtandi in the US and has exclusive marketing rights in the rest of the world. Its Marketing Authorization Application for Xtandi is currently under review by the European Medicines Agency.

While early-stage prostate cancer can frequently be cured by surgery or radiation therapy, there is no cure for prostate cancer once these therapies have failed. Blocking the biosynthesis or action of testosterone and its active metabolite dihydroxytestosterone has long been a strategy to combat prostate cancer; consequently, androgen-receptor (AR) antagonists like AstraZeneca’s Casodex (bicalutamide) and gonadotropin-releasing hormone agonists like AstraZeneca’s Zoladex (goserelin) are well established in the prostate cancer treatment algorithm. The most advanced form of prostate cancer, mCRPC, no longer responds to treatment with primarily hormone therapies like these. Taxotere, a type of chemotherapy, is currently the gold-standard first-line treatment for mCRPC.

Xtandi is a next-generation androgen-receptor antagonist. Like traditional AR antagonists, the drug inhibits the binding of testosterone to the AR. However, it also inhibits the AR’s ability to perform other functions within the cell. The FDA approval is based on data from the 1,199-patient Phase III AFFIRM trial, in which men with mCRPC previously treated with Taxotere were randomized 2:1 to Xtandi or placebo. Patients responded to Xtandi so well that an independent analysis data committee recommended that the trial be stopped and all patients be offered Xtandi. Patients treated with Xtandi demonstrated an estimated median overall survival of 18.4 months compared to 13.6 months for patients taking the placebo. The radiographic progression-free survival time was 8.3 months for patients taking Xtandi versus 2.9 months in the placebo arm. Patients taking Xtandi had a favorable soft-tissue response rate (28.9% versus 3.8%) as well as a longer time to PSA progression (8.3 months versus 3.0 months). Xtandi’s safety profile is excellent, as serious adverse events were more common in the placebo arm, which is highly unusual for a cancer drug. The most common side effects were relatively mild, and included diarrhea, hot flush, and fatigue. Since a very small percentage (0.9%) of patients taking Xtandi experienced seizures, Medivation and Astellas will conduct an open-label safety study of Xtandi in patients at high risk for seizures to fulfill the FDA’s post-marketing requirement.

Xtandi’s exceptional safety profile, attractive oral administration, and ability to prolong the overall survival of men with mCRPC will surely be drivers of its success when it hits the market in mid-September. The drug will face major competition from Johnson & Johnson’s Zytiga (abiraterone acetate), another orally administered drug with a good safety profile that is currently approved for men with mCRPC who have failed docetaxel therapy. Still, Xtandi’s uptake is expected to be swift. Johnson & Johnson’s supplemental new drug application (sNDA) to gain FDA approval for Zytiga in the chemotherapy-naïve mCRPC population has already been accepted, and approval is expected by the end of the year. GlobalData expects that after it is approved for this indication, Zytiga will become the gold-standard first-line treatment for mCRPC, and Xtandi will become the treatment of choice for patients refractory to docetaxel.

While Xtandi will initially be used to treat patients who have failed treatment with Taxotere, Medivation and Astellas are currently operating a battery of trials to extend Xtandi’s use to earlier in the treatment sequence. Like Johnson & Johnson, the companies will next seek approval of Xtandi for chemotherapy-naïve patients with mCRPC with data from the Phase III PREVAIL trial. Results are expected in early 2014. In addition, the companies are operating Phase I and II trials investigating Xtandi much earlier in the treatment algorithm. This includes its use in patients who have never received any hormonal therapy, and as neoadjuvant therapy to radical prostatectomy. Positive data from these trials will dramatically increase the number of patients eligible for Xtandi therapy, and maximize the drug’s potential revenue.

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