Categories
Uncategorized

Enzalutamide (XTANDI)

An androgen receptor antagonist drug developed for the treatment of castration-resistant prostate cancer.

Can be used in all patients with metastatic PC .

 

First generation anti-androgens exert the antitumor activity via competitive inhibition of the androgen receptor. 

Enzalutamide provides a more comprehensive blockade, by multifocal signaling inhibition of the androgen receptor.

An oral androgen receptor inhibitor.

Drug designed to overcome resistance to first generation anti-androgens and avoid antagonist-to-agonist conversion, which can be seen often with first-generation anti-androgens.

Enzalutamide is a targeted androgen receptor inhibitor that competitively binds to the ligand-binding domain of the androgen receptor and inhibits androgen receptor translocation to the cell nucleus, recruitment of androgen receptor cofactors, and androgen receptor binding to DNA.

Prostate cancer relies on androgen receptor signaling for growth throughout the disease continuum.

Has activity in all three steps of the androgen receptor signaling pathways-androgen receptor binding to androgen, androgen receptor nuclear translocation, and androgen receptor DNA binding and coactivator recruitment.

A non-steroidal anti-androgen agent.

It’s use improves survival among patients with previous chemotherapy with docetaxel and the incidence of adverse events of grade 3 or higher was lower among patients receiving this agent then those receiving placebo.

It blocks expression of 11beta hydroxysteroid dehydrogenase-2 in prostate cancer leading to increased interest intratumoral cortisol concentrations.

Targets signaling through the androgen receptor at multiple sipes: inhibits binding of androgens to the androgen receptor, inhibits nuclear translocation of the androgen receptor and DNA.

Inhibits the androgen receptor at 3 points in the signaling pathway.

An androgen receptor agonist that inhibits the receptor’s nuclear translocation and DNA binding, therefore preventing androgen-induced signaling.

Does not require concomitant use of steroids.

Drug absorption is not affected by food intake.

Reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine.

Enzalutamide demonstrated a high PSA response, with PSA reductions of at least 50% in 54% of patients and at least 90% in 25% of patients.

The most common adverse event associated with this drug was fatigue, reported in 34% of patients.

Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth.

Enzalutamide (XTANDI) is for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

The approval was based on a single randomized, placebo-controlled, multicenter trial enrolling 1199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel.

Extended survival a median of 4.8 months compared with placebo in patients with previously received docetaxel, and extended survival of median of 3.9 months in chemotherapy naïve patients when compared to placebo.

Patients were randomly allocated to receive enzalutamide 160 mg orally once daily or placebo until disease progression, initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal.

The median OS was 18.4 and 13.6 months in the enzalutamide and placebo arms, respectively.

The androgen-receptor blocker enzalutamide improves survival by nearly 30% in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) and delays progression of their disease by more than 80%.

The most common adverse reactions included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

In a phase I/II study Enzalutamide demonstrated anti-tumor activity in patients with castrate resistant prostate cancer, regardless of whether they had received prior chemotherapy.

Enzalutamide retains clinical activity as this second line drug following abiraterone, where as a very abireraterone retains no second line activity following enzalutamide

In the AFFIRM study 1199 patients recruited and randomly assigned to study drug enzalutamide 160 mg per day or placebo: after a median follow-up of 14 months, the median overall survival was significantly longer with the study drug versus placebo, 18.4 versus 13.6 months with a 37% reduction in the risk of death.

Grade 3-4 adverse reactions were reported in 47% of patients treated with enzalutamide and in 53% of those on placebo.

The most frequent adverse events are fatigue, back pain, constipation, and arthralgias.

In a randomized double-blind study PREVAIL, patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer who had not received chemotherapy and who had progressed following hormonal therapy received enzalutamide or placebo: The study drug significantly delayed progression of metastatic disease by 81% improvement in the risk of progression or death.

In the above study enzalutamide increased radiographic progression free survival in patients with liver or lung metastases.

Enzalutamide resulted in a 71% reduction in metastatic disease risk among men with castration-resistant prostate cancer (CRPC) and rapid prostate-specific antigen (PSA) doubling time, according to the first interim analysis of data from the phase III PROSPER trial.

The median PSA doubling time for men in the study was 3.7 months.

The PROSPER study: A total of 1,401 men were randomized 2:1 to receive androgen deprivation therapy plus either enzalutamide (160 mg/day) or placebo.

PROs Recommend Enzalutamide as a Treatment Option for High-Risk, Nonmetastatic CRPC

There is clinical benefit of using enzalutamide for the treatment of patients presenting with high-risk, nonmetastatic castration-resistant prostate cancer

In the PROSPER trial, enzalutamide significantly improved metastasis-free survival in patients with non-metastatic, castration-resistant prostate cancer.

Patients aged ≥18 years with nonmetastatic CRPC and a prostate-specific antigen doubling time of up to 10 months were randomized in a 2:1 ratio to receive enzalutamide in the phase 3, double-blind, placebo-controlled PROSPER trial.

The primary end point of the study, reported elsewhere, was metastasis-free survival, and the secondary end points included pain progression

Time to clinically meaningful pain progression was longer with enzalutamide than with placebo, median 36.83 months.

Patients with non-metastatic CRPC receiving enzalutamide had longer metastasis-free survival than did those who received placebo, while maintaining low pain levels and prostate cancer symptom burden and high health-related quality of life,

It showed a clinical benefit by delaying pain progression, symptom worsening, and decrease in functional status, compared with placebo.

Median MFS was 36.6 months with enzalutamide vs 14.7 months with placebo

Patients in the enzalutamide group also saw significantly prolonged time to PSA progression median 37.2 vs 3.9 months; and time to first use of new antineoplastic therapy, median 39.6 vs 17.7 months.

The proportion of progression events in the enzalutamide arm was 50% less than that of the placebo arm.

Median metastatic free survival was 22 months longer with enzalutamide than with placebo.

Median overall survival was not reached for either group but patients in the enzalutamide group had a 20% lower relative mortality risk than those in the placebo group.

Adding enzalutamide to the current standard of care may significantly improve overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (HSPC) according to an interim analysis of the international randomized phase III ENZAMET study.

Researchers found that 80% of men with metastatic HSPC who received this nonsteroidal anti-androgen drug along with the standard-of-care treatment were alive after 3 years compared with 72% of men who received other nonsteroidal anti-androgen drugs along with standard treatment.

Enzalutamide is a more effective inhibitor of the androgen receptor compared with bicalutamide, nilutamide, or flutamide.

When added to testosterone suppression increases overall survival in patients with high and low volume of disease.

In the ENZAMET TRIAL it was associated with significantly longer progression free and overall survival then standing therapy in men with metastatic, hormone sensitive prostate cancer receiving andogen deprivation therapy.

Men with metastatic HSPC were randomly assigned to receive an injection of a testosterone suppression agent (goserelin, leuprolide, or degarelix) with either a 160-mg enzalutamide pill daily or one of three standard Nonsteroidal antti-androgens (bicalutamide, nilutamide, or flutamide).

Overall, there was a 33% decrease in the risk of death in men receiving enzalutamide compared with those who received another nonsteroidal anti-androgen drug.

The increase in survival with enzalutamide was most obvious in men who did not receive docetaxel.

Among patients who received enzalutamide without docetaxel, 83% were alive compared with 70% taking another nonsteroidal anti-androgen drug.

PROSPER trial: Enzalutamide plus androgen deprivation therapy resulted in a longer median overall survival then placebo plus androgen deprivation among men with non-metastatic, castrate resistant prostate cancer and rapidly rising PSA level.
Enzalutamide monotherapy had significant treatment response in patients with low risk or intermediate risk localized prostate cancer and is an alternative treatment option for patients undergoing active surveillance (ENACT Trial).

In the above study the risk of death associated with enzalutamide was 27% lower than the placebo.

In patients with PC with high risk biochemical recurrence (doubling time PDA of less than nine months) enzalutamide plus leuprolide was superior toleuprolide alone with respect to metastasis free survival, and enzalutamide monotherapy was superior to leuprolide alone(Freeland SJ).

Seizures occurred in 0.9% of patients on enzalutamide.

Has potential for seizure activity. 

Seizures thought to be a off target effect of gamma aminobutyric acid A inhibition and this drug should be avoided in patients with underlying conditions that predispose to seizures.

The recommended dose and schedule for enzalutamide is 160 mg orally once daily (four 40 mg capsules).

Leave a Reply

Your email address will not be published. Required fields are marked *