Dr. med. Dirk Manski



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Enzalutamide: Antiandrogen for Castration Resistant Prostate Cancer

Indications for Enzalutamide

Castration-sensitive metastatic prostate carcinoma (M1 CSPC):

Enzalutamide (as of 10/2019) is not approved for the treatment of castration-sensitive metastatic prostate cancer. However, approval is expected based on data from the ENZAMET trial: standard hormone therapy (with or without chemotherapy) with enzalutamide versus standard hormone therapy (with or without chemotherapy) with placebo improved the survival rate of 80% versus 72% after three years, 167 versus 320 patients had a clinical progress(Davis et al, NEJM 2019).

Castration-resistant non-metastatic prostate cancer (M0 CRPC):

Enzalutamide is a treatment option for patients with rising PSA levels under androgen deprivation therapy without metastasis in imaging studies (scintigraphy, CT). The approval is limited to patients at high risk: PSA doubling time under 10 months. In the PROSPER trial, 23% of patients with enzalutamide plus androgen deprivation therapy developed metastases or died, compared to 49% with placebo plus androgen deprivation therapy. Metastasis-free survival was 37 months with enzalutamide versus 15 months with placebo (Hussein et al, 2018).

Castration-resistant metastatic prostate cancer (M1 CRPC):

Enzalutamide is a treatment option for metastatic castration-resistant prostate cancer. In patients after docetaxel chemotherapy, enzalutamide prolonged progression-free survival (8.3 vs. 3.0 months) and overall survival (18.4 vs. 13.6 months) compared to placebo (Scher et al, 2012). The PREVAIL study also demonstrated a high efficacy of enzalutamide prior to chemotherapy in castration-resistant prostate cancer: longer progression-free survival, hence subsequent need for chemotherapy, which was even more successful in the enzalutamide group (Beer et al, 2014). Enzalutamide is approved for chemotherapy-naïve patients since 2014.

Mechanism of Action of Enzalutamide

Enzalutamide inhibits the signal transduction of the androgen receptor:

Pharmacokinetics of Enzalutamide

98% plasma protein binding, hepatic metabolism of enzalutamide mainly via CYP2C8, half-life 3–10 days, renal and fecal excretion of the inactive metabolites.

Side Effects of Enzalutamide

The most common side effects of enzalutamide are hot flushes, diarrhea and headache. Less common are hallucinations, anxiety, cognitive disorders, itching, neutropenia, falls with fractures, hypertension and epilepsy.

Interactions with Enzalutamide

Enzalutamide is a potent enzyme inducer, so caution is recommended with many drug groups such as antiepileptics or oral anticoagulation.

Contraindications for Enzalutamide

Dosage of Enzalutamide

160 mg enzalutamide (four 40 mg capsules) p.o. once a day. The addition of prednisolone is possible, but not necessary. Discontinue treatment in patients with progressive disease or intolerance to enzalutamide.

Brand Name of Enzalutamide:

Xtandi







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References

Beer, T. M.; Armstrong, A. J.; Rathkopf, D. E.; Loriot, Y.; Sternberg, C. N.; Higano, C. S.; Iversen, P.; Bhattacharya, S.; Carles, J.; Chowdhury, S.; Davis, I. D.; de Bono, J. S.; Evans, C. P.; Fizazi, K.; Joshua, A. M.; Kim, C.-S.; Kimura, G.; Mainwaring, P.; Mansbach, H.; Miller, K.; Noonberg, S. B.; Perabo, F.; Phung, D.; Saad, F.; Scher, H. I.; Taplin, M.-E.; Venner, P. M.; Tombal, B. & Investigators, P. R. E. V. A. I. L.
Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med, 2014, 371, 424-433.


Scher, H. I.; Fizazi, K.; Saad, F.; Taplin, M.-E.; Sternberg, C. N.; Miller, K.; de Wit, R.; Mulders, P.; Chi, K. N.; Shore, N. D.; Armstrong, A. J.; Flaig, T. W.; Fléchon, A.; Mainwaring, P.; Fleming, M.; Hainsworth, J. D.; Hirmand, M.; Selby, B.; Seely, L.; de Bono, J. S. & Investigators, A. F. F. I. R. M.
Increased survival with enzalutamide in prostate cancer after chemotherapy.
2012, 367, 1187-1197.


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