Enzalutamid (2) – Xtandi®

• Clinical trials
  • To demonstrate the additional benefit of enzalutamide, the pharmaceutical manufacturer submitted the results of the randomised, double-blind, placebo-controlled PREVAIL trial.

Adult men with metastatic castration-resistant prostate cancer who are asymptomatic or have mild symptoms following failure of androgen deprivation therapy, and for whom chemotherapy is not yet clinically indicated

• For adult men with metastatic castration-resistant prostate cancer who are asymptomatic or have mild symptoms following failure of androgen deprivation therapy, and for whom chemotherapy is not yet clinically indicated, there is an indication for considerable additional benefit for enzalutamide.
• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• mortality
  • For the co-primary endpoint of overall survival, the primary analysis (data cut-off 16 September 2013 following 540 deaths) revealed a significant difference in favour of enzalutamide, with an absolute difference of a median of 2.2 months (hazard ratio (HR): 0.71 [95% confidence interval (CI): 0.60; 0.84]; p-value < 0.001).
  • Overall, the G-BA concludes that, for the endpoint category of mortality, enzalutamide offers considerable additional benefit compared with the appropriate comparator therapy, as a moderate prolongation of survival has been demonstrated.
• Morbidity – time to first skeletal-related complication
  • The secondary endpoint ‘time to first skeletal-related complication’ comprises the individual components ‘time to first bone radiotherapy’, ‘time to first bone surgery’, ‘time to first pathological bone fracture’, ‘time to first spinal cord compression’ and ‘time to first change in antineoplastic therapy for the treatment of bone pain’.
  • This was true both for the overall score (HR: 0.72 [95% CI: 0.61; 0.84]; p < 0.001) and for the individual components ‘time to first bone radiotherapy’ (HR: 0.69 [95% CI: 0.57; 0.84]; p < 0.001) and ‘time to first change in antineoplastic therapy for the treatment of bone pain’ (HR: 0.45 [95% CI: 0.25; 0.83]; p = 0.01) showed statistically significant differences in favour of enzalutamide.
  • However, with the exception of ‘time to first bone radiotherapy’ in the comparator arm, the median time to the first event was not reached for any of the individual components in either study arm. The data must therefore be regarded as immature and cannot be conclusively assessed.
• Morbidity – Pain (BPI-SF)
  • Pain was assessed using the BPI-SF questionnaire (Brief Pain Inventory – Short Form).
  • As the difference between the two treatment arms among the patients not included in the analysis was more than 15% at the evaluation time points presented in the dossier, no valid conclusions regarding this endpoint can be drawn from the study results.
• Health-related quality of life – FACT-P
  • Health-related quality of life was assessed in the PREVAIL study using the FACT-P (Functional Assessment of Cancer Therapy – Prostate) questionnaire, which has been validated for the indication of prostate cancer.
  • In the benefit assessment, the time to deterioration in quality of life (assessed using the FACT-P) is taken into account, as this analysis adequately accounts for the major differences in observation periods between the treatment arms (median 16.6 months in the intervention arm vs. 4.6 months in the control arm) are adequately taken into account.
  • With regard to the total FACT-P score, there is a statistically significant advantage for enzalutamide (HR: 0.62 [95% CI: 0.54; 0.72]; p < 0.001); patients in the enzalutamide arm showed a relevant deterioration in their score of at least 10 points, on a median basis, 5.7 months later than those in the control arm. For all five subscales of the questionnaire, including the prostate cancer-specific subscale, a significantly later deterioration of at least 3 scale points was also observed in patients treated with enzalutamide.
  • In the quality of life endpoint category, an overall analysis of the FACT-P questionnaire results shows that a deterioration in health-related quality of life occurs significantly later with enzalutamide treatment than with the treatment administered in the comparator arm.
• Side effects
  • For the safety endpoints of severe adverse events of CTCAE grade ≥ 3 (HR: 0.66 [95% CI: 0.57; 0.77]; p < 0.001), serious adverse events (HR: 0.63 [95% CI: 0.53; 0.76]; p < 0.001) and discontinuation due to an adverse event (HR: 0.35 [95% CI: 0.28; 0.44]; p < 0.001).
  • These positive results are offset by a statistically significant disadvantage of enzalutamide with regard to the non-serious side effect ‘hot flushes’ (HR: 2.29 [95% CI: 1.73; 3.05]; p < 0.001).
  • Taking the results for the individual endpoints into account, a considerable additional benefit is identified for enzalutamide in the ‘side effects’ endpoint category, as there is a significant reduction in serious side effects.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of enzalutamide as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease. Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit not previously achieved, as it entails a moderate prolongation of overall survival, a reduction in serious symptoms relating to skeletal complications and disease-related pain, a significant reduction in side effects, and, furthermore, a delay in the deterioration of health-related quality of life.
  • However, when the available results on mortality, morbidity and quality of life, together with the findings on side effects, are considered as a whole, enzalutamide does not demonstrate a sustained and, compared with the appropriate comparator therapy, previously unattained major improvement in treatment-related benefit; in particular, it does not result in a cure of the disease, no significant prolongation of life, no long-term freedom from severe symptoms and no substantial avoidance of serious side effects. Therefore, classification as ‘major additional benefit’ is not justified.

Courtesy translation only, please refer to the German original.