Updated Analysis of Prostate Cancer Trials Continue to Demonstrate Benefit with Xtandi

Two studies investigating Xtandi (enzalutamide) in men with early-stage metastatic castration-resistant prostate cancer (mCRPC) further confirmed the overall survival (OS) and progression-free survival (PFS) benefit of the agent over placebo, according to late-breaking results from the phase 3 PREVAIL and phase 2 TERRAIN studies that were presented during a plenary session of the European Association of Urology in Madrid, Spain.

Bertrand Tombal, head of urology, Saint-Luc University Hospital, Brussels, Belgium, presented an updated analysis of the OS data from the PREVAIL trial. In PREVAIL, researchers compared Xtandi to placebo in men with mCRPC with progression after androgen deprivation therapy (ADT). The co-primary endpoints of the trial were OS and radiographic PFS in patients administered 160 mg of Xtandi once daily versus placebo.

Results from PREVAIL confirmed the value and anti-tumor efficacy of Xtandi, noted Tombal. Patients demonstrated an objective response rate of 59 percent and a quality of life response rate of 40 percent. In the updated OS analysis, researchers found a 23 percent reduction in risk of death and a four-month improvement in median survival with Xtandi (35.3 months) over placebo (31.3 months).

The interim analysis, presented during the 2014 Genitourinary Cancers Symposium, showed a statistically significant benefit of Xtandi over placebo with a 30 percent reduction in risk of death and an 81 percent reduction in risk of radiographic progression or death.

The findings could “profoundly change the early mCRPC landscape,” said Tombal during his presentation. “By starting treatment in asymptomatic patients, there is a significant delay in symptomatic disease progression and an overall survival benefit.”

But the issue of resistance still needs to be addressed, with a need for biomarkers to identify patients with primary resistance, said Maria De Santis, during the presentation. De Santis is a senior resident in oncology, Center of Oncology and Hematology at the Kaiser Franz Josef Hospital, Austria. Adverse events of enzalutamide are also a cause for concern as almost 50 percent of patients suffer from fatigue as a result of the treatment. These concerns are important research topics for the future, acknowledged Tombal.

In the second Xtandi study, Axel Heidenreich, professor in the department of urology at University Hospital Aachen, Germany, presented the latest data from TERRAIN, which compared Xtandi with bicalutamide in early mCRPC. The primary endpoint of the trial was PFS, defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, or the initiation of new anti-neoplastic therapy or death, whichever occurred first. Findings demonstrated the benefits of Xtandi in PFS and delayed PSA progression.

The study achieved its primary objective of a statistically significant increase in PFS for Xtandi compared with bicalutamide. The median PFS for patients in the Xtandi arm was 9.9 months longer compared with patients who received bicalutamide (15.7 versus 5.8 months, respectively). The median time to PSA progression was 13.6 months longer with Xtandi (19.4 months) relative to bicalutamide treatment (5.8 months). The median time on Xtandi treatment was 11.7 months compared with 5.8 months on bicalutamide.

Of concern, however, are the adverse effects associated with Xtandi, which are more prominent than those of bicalutamide, said Alberto Briganti, Vita-Salute San Raffaele University Hospital, Milan. In the topline study results of TERRAIN, incidence of grade 3 adverse events were 5.5 percent and 2.1 percent in the Xtandi and bicalutamide arms, respectively. In addition, diarrhea, fatigue, hot flush, hypertension, pain in extremities, and weight loss all occurred more frequently in the Xtandi arm.

Briganti further argued that the results of this study were to be expected because it has been shown that the mechanism of enzalutamide is much more effective in managing mCRPC. “This trial is an easy way to demonstrate the efficacy of one drug over another,” Briganti says.

Heidenreich said that there was never any evidence that bicalutamide was effective in mCRPC. Based on the results, it appears that Xtandi is an effective alternative to treat patients. A final issue raised by Briganti and acknowledged by Heidenreich is that, in some countries, the decision to treat with Xtandi is not in the hands of urologists but in those of medical oncologists.