Enzalutamide (MDV3100), trade name Xtandi, was first approved in the United States on August 31, 2012, for patients with advanced prostate cancer after failure of chemotherapy with the antineoplastic drug docetaxel.
On September 10, 2014, the U.S. Food and Drug Administration (FDA) granted additional approval for enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy, mCRPC) patients who have not received chemotherapy.
What is enzalutamide?
Enzalutamide is a second-generation androgen receptor antagonist, a novel drug that targets the androgens receptor (AR) signaling pathway, acting at different stages of the AR signaling pathway, inhibiting the binding of androgens to their receptors, and inhibiting the nuclear translocation of AR and its interaction with DNA.
Clinical trials confirm that enzalutamide effectively prolongs survival
Pivotal clinical trials in which enzalutamide was approved by the FDA include the AFFIRM trial and the PREVAIL trial:
AFFIRM trial: 37% reduction in risk of death compared to placebo
A total of 1199 patients with CRPC were enrolled in 15 countries in the phase III AFFIRM clinical trial study and randomized into 2 groups, the enzalutamide group (800 patients), and the placebo group (399 patients).
A post-blinding analysis of the study showed that the median overall survival (OS) was 18.4 months in the enzalutamide group compared with 13.6 months in the placebo group, with a significant difference of 37% risk reduction in the enzalutamide versus placebo group.
The enzalutamide group outperformed the placebo group on other measures, including rate of decline in PSA values, soft tissue response rate, quality of life, time to prostate specific antigen (PSA) progression, time to first skeletal-related event, and progression-free survival on imaging.
PREVAIL trial: 29% reduction in risk of death compared with placebo
The PREVAIL trial, another randomized, double-blind, placebo-controlled phase III clinical study, enrolled 1717 patients with CRPC, randomized to 872 in the enzalutamide group and 845 in the placebo group, and showed a median OS of 32.4 months and 30.2 months in the two groups, respectively; mortality was lower in the enzalutamide group than in the placebo group (28% vs 35%), and the enzalutamide group had a lower risk of death compared with the placebo group. The risk rate was reduced by 29% in the enzalutamide group versus the placebo group.
The benefit of enzalutamide was also confirmed on other metrics: time to initiation of cytotoxic chemotherapy, time to first skeletal-related event, soft-tissue response rate, time to PSA progression, and rate of 50% PSA decline.
Therefore, the PREVAIL study showed that enzalutamide significantly prolonged survival in patients with CRPC after failure of docetaxel chemotherapy.
Compared to chemotherapy, enzalutamide has fewer adverse effects
Unlike chemotherapy drugs that kill tumor cells while also damaging normal cells, enzalutamide, as a molecularly targeted drug, works primarily on tumor cells with specific targets, so adverse reactions are very small and largely resolve with symptomatic management.
Common adverse reactions include: weakness/fatigue, back pain, diarrhea, arthralgia, hot flashes, peripheral blood edema, musculoskeletal pain, headache, upper respiratory tract infection, muscle weakness, vertigo, insomnia, lower respiratory tract infection, spinal cord compression and cauda equina syndrome, hematuria, sensory abnormalities, anxiety, and hypertension. Epilepsy has been reported in some cases, but the incidence is only 0.9%.
What should I look for in treatment with enzalutamide?
What should I know about treatment with enzalutamide?
- Enzalutamide is a capsule formulation of 40 mg per capsule with a recommended clinical dose of 160 mg/d (4 capsules per day) before and after meals for 8 months. Be careful to swallow the capsule whole and not chew, dissolve, or open it.
- If patients experience toxic reactions or intolerable adverse reactions, the drug may be discontinued for 1 week or until symptoms resolve and the original dose or a lower dose (120 mg or 80 mg) may be reintroduced.
- Enzalutamide may be used in patients with mild to moderate hepatic insufficiency (Child-Pugh classifications A and B) or mild to moderate renal insufficiency (creatinine clearance 30-89 ml/min).
Previous treatment with abiraterone/docetaxel may affect enzalutamide efficacy
In recent years, studies have evaluated the effect of 310 patients with CRPC treated with abiraterone/docetaxel followed by enzalutamide. They were divided into 4 groups:
- Group A: No prior treatment with abiraterone and docetaxel (12%);
- Group B: Treated with abiraterone (25%);
- Group B: Treated with abiraterone (25%);
- Group C: Treated with docetaxel (10%);
- Group C: Treated with docetaxel (10%);
- Group D: treated with abiraterone and docetaxel (53%).
The percentages of patients receiving different treatment modalities with OS beyond 12 months were 78%, 64%, 77%, and 51%, respectively; PSA progression-free survival was 5.5 months, 4 months, 4.1 months, and 2.8 months, respectively; and PSA response rates ≥30% were 67%, 28%, 43%, and 24%, respectively.
On all three efficacy measures, patients in group A who had not been treated with abiraterone and docetaxel were significantly better than those in the other groups. This suggests that prior use of docetaxel or abiraterone may have reduced the antitumor activity of enzalutamide, and the reason for this may be related to cross-resistance between these drugs.
Enzalutamide and abiraterone, how should I choose?
Enzalutamide and abiraterone are both oral antiandrogenic drugs, and both have the advantage of being easy to use and having fewer adverse effects. For specific use, enzalutamide does not need to be combined with steroids (e.g., prednisone, dexamethasone) and is more appropriate for patients for whom steroids are not recommended; abiraterone is more appropriate for patients with a history of seizures or for patients being treated with such medications to lower the seizure threshold.
Of course, the above issues require more relevant clinical trials to advance their rational use in patients with CRPC.
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