PREVAIL, TERRAIN Updates Show Improved OS With Enzalutamide

Bertrand Tombal, MD

Two studies investigating 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 III PREVAIL and phase II TERRAIN studies that were presented during a plenary session of the European Association of Urology in Madrid, Spain.

Bertrand Tombal, MD, 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 enzalutamide 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 enzalutamide once daily versus placebo.

Results from PREVAIL confirmed the value and anti-tumor efficacy of enzalutamide, noted Tombal. Patients demonstrated an objective response rate of 59% and a quality of life response rate of 40%. In the updated OS analysis, researchers found a 23% reduction in risk of death (HR = 0.77; 95% CI, 0.67-0.88; P = .0002) and a 4-month improvement in median survival with enzalutamide (35.3 months [95% CI 32.2 - not yet reached]) over placebo (31.3 months [95% CI 28.8 -34.2]).

The interim analysis, presented during the 2014 Genitourinary Cancers Symposium, showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (HR = 0.70; 95% CI, 0.59-0.83; P <.0001) and an 81% reduction in risk of radiographic progression or death (HR = 0.19; 95% CI, 0.15-0.23; P <.0001).

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, MD, 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% 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 enzalutamide study, Axel Heidenreich, MD, professor in the department of urology at University Hospital Aachen, Germany, presented the latest data from TERRAIN, which compared enzalutamide 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 enzalutamide in PFS and delayed PSA progression.

The study achieved its primary objective of a statistically significant increase in PFS for enzalutamide compared with bicalutamide. The median PFS for patients in the enzalutamide arm was 9.9 months longer compared with patients who received bicalutamide (15.7 vs 5.8 months, respectively) with a HR of 0.44 (95% CI, 0.34-0.57). The median time to PSA progression was 13.6 months longer with enzalutamide (19.4 months) relative to bicalutamide treatment (5.8 months) with an HR of 0.28 (82% of enzalutamide-treated patients achieved ≥ 50% PSA reduction from baseline by week 13 versus 21% of bicalutamide-treated patients). The median time on enzalutamide treatment was 11.7 months compared with 5.8 months on bicalutamide.

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

Heidenreich said that there was never any evidence that bicalutamide was effective in mCRPC. Based on the results, it appears that enzalutamide 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 enzalutamide is not in the hands of urologists but in those of medical oncologists.