Xtandi PREVAILs in Metastatic Castrate-Resistant Prostate Cancer

Prostate cancer is the most common cancer in men and the second most common cause of cancer deaths in men in the United States. The incident population of prostate cancer in the United States was above 200,000 patients in 2013.1 The rate of prostate cancer growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone.

Perhaps the most important recent advances in treatment of prostate cancer are the development and approvals of the next generation anti-androgens, Xtandi® (enzalutamide, Medivation/Astellas), FDA approved in August 2012 for treatment of metastatic castrate-resistant prostate cancer (mCRPC) in the post-docetaxel setting, and Zytiga® (abiraterone, Johnson & Johnson), FDA-approved in April 2011 in the post-docetaxel setting and subsequently approved in December 2012 to include use in the chemotherapy-naïve mCRPC setting. Approval of these two next-generation anti-androgens set the scene for an epic battle for market share between these agents.

Impressive results from the international Phase III PREVAIL study were presented Thursday January 30, 2014, at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium by Dr. Tomasz Beer.2 PREVAIL, a randomized, placebo-controlled Phase III trial was designed to evaluate safety and efficacy of Xtandi versus placebo in patients with mCRPC. A total of 1,717 men who were asymptomatic or mildly symptomatic and chemotherapy-naïve were randomized to receive either Xtandi (n=872) or placebo (n=845). Co-primary endpoints were overall survival and radiographic progression-free survival (rPFS). The trial design included one planned interim analysis at approximately 516 events. The Independent Data Monitoring Committee analyzed the data following 540 deaths and reported significant benefits in overall survival and rPFS for patients in the Xtandi arm. Following this interim analysis, PREVAIL was halted, unblinded, and patients in the placebo arm were offered treatment with Xtandi.

The median duration of treatment was more than three-fold longer for the Xtandi arm at 16.6 months versus 4.6 months for the control arm. rPFS was estimated at 13.8 months for the Xtandi arm versus 3.9 months for the placebo arm (HR=0.186; p < 0.0001) and this benefit favored Xtandi across all subgroups of patients (including performance status, age, geographic region, and presence of visceral disease). Treatment with Xtandi also provided a significant 29% improvement the risk of death, with an estimated 32.4 months median overall survival in the Xtandi arm compared with an estimated 30.2 months for the placebo arm (HR=0.706; p<0.0001). This improvement in overall survival came despite the fact that more patients from the placebo arm (70.3%) received at least one subsequent life-extending therapy compared with just 40.3% of patients in the Xtandi arm. Again, the survival advantage provided by Xtandi was consistent across all patient subgroups. Xtandi therapy yielded an objective response rate of 58.8%, including a complete response rate of 19.7%, compared with an objective response rate of only 4.9% and a 1% complete response rate in the placebo arm. Xtandi also delayed the median time to initiation of chemotherapy by 17 months (28.0 months versus 10.8 months). Xtandi was well tolerated in this trial, with the most common adverse events reported as fatigue, back pain, constipation and arthralgia, most of which were low grade. Other adverse events of interest that were slightly more prevalent in the Xtandi arm included cardiac adverse events, and hypertension, again, mostly low grade. Seizures were reported in one patient from each treatment arm.

With strongly positive results from PREVAIL in hand, Medivation and Astellas will waste no time with their regulatory submissions to expand the label of Xtandi to include chemotherapy naïve mCRPC.  Upon approval, Xtandi will join Zytiga and Provenge® (sipuleucel-T, Dendreon) as the only approved agents to treat mCRPC prior to docetaxel therapy.  How physicians will choose which drug to use initially, and the ideal sequence of therapies over the course of the disease, is currently one of the most asked questions in the prostate cancer field.  If we look strictly at clinical outcomes in the two pivotal Phase III trials in chemotherapy-naïve mCRPC (keeping in mind the usual caveats about cross-trial comparisons), both Xtandi and Zytiga significantly improve rPFS (with potentially stronger benefit in the Xtandi trial) but slight differences exist with regard to impact on overall survival ― Zytiga offers a 5.2 month OS benefit that failed to reach statistical significance,3 while Xtandi offers a 2.2 month OS benefit that did reach statistical significance.  Which of these outcomes will prove more meaningful and convincing to physicians and patients who are weighing their options between multiple effective agents, and what other factors will come into play in such decisions?  With both drugs projected to be blockbusters, this truly is the billion dollar question.  Other factors to be considered include:

  • Safety: the toxicity profile of each drug is great in comparison with chemotherapy, but small differences exist between the two with regard to liver, cardiovascular, and seizure events)
  • Use of concomitant corticosteroids: Zytiga requires this, Xtandi does not
  • Cost of therapy: Xtandi is slightly more expensive on a monthly basis
  • Sequencing of the two agents: there remains limited data to understand whether one sequence is more effective than the other, but this is a hotly debated topic
  • Secondary endpoints: time delay to initiation of chemotherapy may hold significant influence with physicians, and the data for this endpoint appear stronger for Xtandi (17.2-month benefit over placebo) than was reported with Zytiga (8.4-month benefit over placebo)
  • Physician specialty: urologists and oncologists are both key treaters of mCRPC, but the influential factors that guide treatment decisions may differ between these specialists

There remain a lot of unknowns with regard to the future treatment paradigms for mCRPC.  But one thing remains certain: the pace of development, level of competition, and clinical improvements in prostate cancer are growing by leaps and bounds, and the patients will reap the greatest rewards.


1 Kantar Health CancerMPact® United States Patient Metrics, accessed January 30, 2014.

2 Beer TM, et al., Abstract LBA1, ASCO GU Symposium 2014.

3 Zytiga FDA label, accessed January 30, 2014.

By: Stephanie Hawthorne, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health

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