Enzalutamide (Xtandi®) prolongs survival in men whose metastatic castration-resistant prostate cancer is progressive after chemotherapy. But is the oral androgen receptor pathway inhibitor also effective in patients who have already received androgen deprivation but not yet chemotherapy? Finally, therapies that are less toxic and thus accessible to those patients who tolerate chemotherapy poorly (e.g., due to preexisting comorbidities) are urgently needed. An update of the PREVAIL study at the EAU Congress in Madrid [1] confirmed the good results of the interim analysis from 2014 [2].
The double-blind phase III study included a total of 1717 patients with metastatic prostate cancer who showed progression in PSA and/or radiographically while receiving therapy with LHRH analogues or after orchiectomy. They were randomized to receive either enzalutamide at a dose of 160 mg or placebo, each once daily. ECOG performance status was grade 0 or 1. The men were either asymptomatic or suffered from mild symptoms. Continued androgen deprivation was considered a requirement for study inclusion. Prior antiandrogenic therapies and concomitant administration of glucocorticoids were allowed. None of the men had previously received cytotoxic chemotherapy, ketoconazole, or abiraterone.
Primary and secondary endpoints
The primary endpoints were radiographic progression-free survival and overall survival. Treatment was given until unacceptable side effects or radiographic progression and thus initiation of chemotherapy or therapy with another agent.
Secondary endpoints included time to initiation of cytotoxic chemotherapy, first skeletal-associated event, PSA progression, and the rate of men with at least a 50% decline in PSA.
Significant extension in survival
After 540 deaths occurred, they performed the planned interim analysis, which showed a clear benefit of active treatment:
- At one year, the rate of radiographic progression-free survival was 65% in the enzalutamide group and 14% in the placebo group, representing an 81% risk reduction (HR 0.19; 95% CI 0.15-0.23; p<0.001).
- Overall survival at the time of data cutoff was 72% in the actively treated group (626 patients) and 63% in the control group (532 patients). The risk of mortality was thus reduced by a significant 29% with enzalutamide (HR 0.71; 95% CI 0.60-0.84; p<0.001). It should be kept in mind that patients in the placebo group had received effective treatment with docetaxel or abiraterone earlier and more frequently than those in the enzalutamide group. Accordingly, at the time of the analysis, many patients had already been treated with additional therapies.
- There were significant benefits for enzalutamide in all secondary endpoints: time to initiation of cytotoxic chemotherapy (HR 0.35), to first skeletal-associated event (HR 0.72), to PSA progression (HR 0.17), and the rate of subjects with at least a 50% decline in PSA (78 vs. 3%).
Side effect profile
The most common, clinically relevant, therapy-associated adverse events were fatigue and hypertension. 43% (enzalutamide) vs. 37% (placebo) of patients experienced a grade 3 or higher event. However, the median time to occurrence of such an event was significantly longer under active treatment (22.3 vs. 13.3 months). In both groups, an equal number of patients discontinued therapy because of an adverse event (6%).
Update at the EAU Congress
Because the results were so clear even then, they unblinded the study and defined the results as definitive. Placebo patients were allowed to switch to the other arm. The update presented at the EAU Congress 2015 clearly confirmed the results of the interim analysis: after 784 deaths, a significant overall survival benefit of four months was shown with enzalutamide (compared with 2.2 months in the interim analysis). Median survival was 35.3 months with enzalutamide and 31.3 months with placebo.
The authors of the 2014 article concluded that the risk of mortality and radiographic progression could be significantly reduced with enzalutamide. In addition, the time to initiation of chemotherapy with the active substance could be delayed by a median of 17 months. The update after 784 deaths confirms the robustness of the results of the initial evaluation.
Literature:
- Tombal B, et al: Late Breaking News Plenary Session at the Annual Meeting of the European Association of Urology (EAU), March 24, 2015, Madrid.
- Beer TM, et al: Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med 2014; 371: 424-433.
InFo ONCOLOGY & HEMATOLOGY 2015; 3(6): 6
