STOCKHOLM — In European men with prostate cancer, the benefit from the androgen-receptor antagonist enzalutamide (Xtandi, Medivation) is similar to that in North American men.
That is the latest message from investigators of the phase 3 PREVAIL trial, which showed "unprecedented" results for the drug in men with castration-resistant prostate cancer and no previous chemotherapy. The findings led to the trial being stopped.
"Enzalutamide delays radiographic progression and prolongs survival in both the full population and the European subpopulation of PREVAIL," investigator Bertrand Tombal, MD, from the Université Catholique de Louvain in Belgium, told Medscape Medical News.
He presented the European subanalysis here at the European Association of Urology (EAU) 29th Annual Congress, and emphasized the similarity between the European and North America results.
"There were no significant differences, and this is what we wanted to highlight," he said.
Dr. Tombal explained that it was important to investigate this because of the failure of another trial in prostate cancer — the ELM-PC 5 trial, which evaluated orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer that had progressed during or after docetaxel-based therapy.
The failure of the ELM-PC 5 trial was attributed to geographic variations, which were said to be linked to unequal access to drugs, as previously reported by Medscape Medical News.
"It appeared to us that, in this context, our PREVAIL data were important to show to reassure European physicians and patients," said Dr. Tombal.
The PREVAIL trial evaluated 1715 men (53% European) with metastatic prostate cancer that was progressing despite androgen-deprivation therapy (ADT). All men were chemotherapy-naïve and asymptomatic or mildly symptomatic.
The coprimary end points of the study were radiographic progression-free survival and overall survival. The men were randomized to receive enzalutamide 160 mg/day (n = 872) or placebo (n = 845).
Significant Benefit in Treatment Group
The trial was halted by the independent data monitoring committee at the planned interim analysis because of a statistically significant benefit in the treatment group.
At the time, coprincipal investigator Tomasz M. Beer, MD, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health & Science University in Portland, stated that, "to my knowledge, the benefits in overall survival and radiographic progression-free survival reported in the PREVAIL trial results are unprecedented in this patient population."
Dr. Beer presented full results earlier this year at the Genitourinary Cancers Symposium.
Data from the PREVAIL trial support the use of enzalutamide as first-line therapy in castration-resistant prostate cancer. It is expected that they will be submitted for approval for this indication.
Currently, the drug is approved for use as second-line therapy after docetaxel chemotherapy in the United States and in Europe on the basis of data from the AFFIRM trial.
Here at the EAU meeting, Dr. Tombal presented results for the European subgroup, as well as for the overall patient population.
When the trial was halted early, at a median follow-up of 20 months, enzalutamide significantly reduced the risk for death by 29% (hazard ratio [HR], 0.7; P < .0001).
Enzalutamide significantly increased radiographic progression-free survival, compared with placebo, to "an unprecedented extent." Progression-free survival increased from 3.9 to 13.8 months in the overall population (HR, 0.19; P < .001); and from 3.8 to 13.8 months in the European subpopulation (HR, 0.21; P < .001), Dr. Tombal reported.
A major benefit for patients was the drug's effect on delaying the onset of chemotherapy, he said. In the overall population, chemotherapy was started after 10.8 months in the placebo group and 28.0 months in the treatment group (HR, 0.35; P < .001); in the European subpopulation, chemotherapy was started after 9.9 and 26.0 months, respectively (HR, 0.34; P < .001).
The difference is almost 1.5 years, which is "a very important delay," he said.
In addition, time to prostate-specific antigen (PSA) progression improved with enzalutamide, compared with placebo, in both the overall population and the European subpopulation (11.2 vs 2.8 months; HR 0.17; P < .001).
Table 1. Decline in PSA From Baseline
| Decline | Treatment Group, % | Placebo Group, % | P Value |
| ≥50% | |||
| Overall population | 78.0 | 3.5 | <.001 |
| European subpopulation | 77.6 | 2.5 | <.001 |
| ≥90% | |||
| Overall population | 48.6 | 1.2 | <.001 |
| European subpopulation | 45.5 | 1.0 | <.001 |
Adverse events of grade 3 or higher were similar in the treatment and placebo groups in the overall population (42.9% vs 37.1%) and in the European subpopulation (45.5% vs 38.8%).
Discontinuation because of adverse events was 5% to 6% in both groups in both populations.
Adverse events leading to death were similar in the treatment and placebo groups in the overall population (4.2% vs 3.8%) and in the European subpopulation (5.6% vs 4.5%).
Table. Adverse Events of Any Grade
| Adverse Event | Treatment Group, % | Placebo Group, % |
| Overall population (n = 1715) | ||
| Fatigue | 35.6 | 25.8 |
| Back pain | 27.0 | 22.2 |
| Constipation | 22.2 | 17.2 |
| Arthralgia | 20.3 | 16.0 |
| Hypertension | 13.4 | 4.1 |
| Cardiac adverse events | 10.1 | 7.8 |
| ALT increased | 0.9 | 0.6 |
| Seizure | 0.1 | 0.1 |
| European subpopulation (n = 910) | ||
| Fatigue | 24.6 | 17.7 |
| Back pain | 25.0 | 19.5 |
| Constipation | 19.2 | 12.3 |
| Arthralgia | 16.6 | 12.6 |
| Hypertension | 13.6 | 4.7 |
| Cardiac adverse events | 9.5 | 6.5 |
| ALT increased | 1.1 | 0.4 |
| Seizure | 0.0 | 0.0 |
"In both the full population and the European population, treatment with enzalutamide significantly delayed the progression of metastatic disease, significantly reduced the risk of death, and significantly delayed the time to initiation of cytotoxic chemotherapy," Dr. Tombal explained. "Safety outcomes in the European population were consistent with those from the full population, and with a quite acceptable profile."
"Enzalutamide added to ADT at progression provides meaningful clinical benefit to men with metastatic prostate cancer," he concluded.
Dr. Tombal disclosed arrangements with Medivation, which makes the drug, as well as Astellas, Amgen, Ferring, Bayer, Sanofi. The other trial investigators report extensive financial relationships, many of them with Medivation.
European Association of Urology (EAU) 29th Annual Congress: Abstract LBA3. Presented April 15, 2014.
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Cite this: European PREVAIL Data Uphold Enzalutamide for Prostate Cancer - Medscape - Apr 16, 2014.
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