Abiraterone acetate

Potent and selective inhibitor of CYP17 alpha hydroxylase and C17-18-lyase activity which are both essential steps in androgen biosynthesis.

Oral agent that is an irreversible inhibitor of CYP17A1 enzyme in the adrenal cortex.

Inhibits extra gonadal androgen synthesis.

Its specific activities block enzymatic reactions that allow conversion of precursor steroids to 5alpha-dihydrotestosterone (DHT).

CYP17A1 inseam is required for the production of dehydroepiandrostendione (DHEA), which is ultimately converted to testosterone in the testis.

CYP17A1 is also present in testicular and prostatic tissue.

Inhibits irreversibly 17ahydroxylase/C17, 20 lyase, a ket enzyme in androgen biosynthesis, and suppresses adrenal and tumor androgens, resulting in undetectable serum testosterone concentration biosynthesis.

Tumors of the prostate required DHT for resistance, so blocking is synthesis improve survival.

Castrate resistant prostate cancer that responds to abiraterone, depends on extragonadal androgen synthesis.

10-30 times more potent inhibitor of CYP17 than ketoconazole.

CYP17 enzyme is key to the generation of androgens and estrogens, in tumor tissue and adrenal glands.

By blocking cytochrome P450 c17 (CYP17 it blocks androgen synthesis by the adrenal glands, testes, and within the prostate tumor.

A phase II COU-AA-004 trial in patients with metastatic hormonally refractive patients after failure of Docetaxel based chemotherapy: at 3 months 45% of patients experienced a 50% decline in PSA.

A phase III COU-AA-310 study revealed a 3.5 months increase in overall survival in patients with metastatic castration resistant prostate cancer who had progressed after treatment with docetaxel, with significant improvements in PSA response rates, in time to PSA progression progression free survival and doubling time to skeletal related events

In chemotherapy naive patients the medication improves survival by a median of 4.4 months compared with placebo.

Reduces serum androgens derived from adrenal and testicular sources.

Attacks the adrenal and extragonadal synthesis of androgen.

Suppresses both circulating and intratumoral androgen levels.

It has a CYP17A inhibitory effect that may result in hypertension and hypokalemia, therefore requiring steroids.

Antigen receptors and ligand-dependent and androgen receptor signaling remaining active and up regulated in men with castrate levels of testosterone.

Inhibits enzymes expressed in testicular, adrenal, and prostatic tumor tissue, which would normally facilitate the conversion of pregnenolone and progesterone to their actibe derivatives, as well as allow for the formation of dehydroepiandrosterone and androstenedione, which are important androgens, but also function as precursors for testosterone.

A prodrug.

Tradename Zytiga.

As a selective inhibitor androgen biosynthesis that blocks cytochrome P450 c17 (CYP17), a critical enzyme in testosterone synthesis, blocking androgen synthesis by the adrenal glands and testes and within the prostate tumor.

The concentration of this agent in microsomes required to produce a 50% inhibition of CYP17 is about 10% of that of ketoconazole (Haidar S, Attard G).

Reduces androgen levels to less than 1 ng/dL.

Surgical orchiectomy or pharmacologic castration with a gonadotropin releasing hormone analogue leads to serum testosterone levels in the range of 20-50 ng per deciliter.

Nonspecific CYP 17 inhibitors ketoconazole and aminoglutethimide improve survival in metastatic breast cancer and each have less favorable safety profile.

Reduces estradiol, dihydroepiandrostenedione and andrstenedione levels.

Phase I study of patients with hormonally refractive prostate cancer (and 58% failed previous ketoconazole) resulted in a 50% or greater reduction in PSA was in 55% of patients (Ryan C).

In a double-blind study, randomly assigning 1088 patients to receive abiraterone acetate 1000 mg plus prednisone 5 mg twice a day or placebo plus prednisone: abiraterone mproved radiographic progression free survival, showed a trend towards improved overall survival, and significantly delayed clinical decline in initiation of chemotherapy in patients with metastatic castration resistant prostate cancer (Ryan CJ et al).

Phase II study of 1000mg/day docetaxel treated patients with hormonally refractive prostate cancer, associated with PSA declines of greater than 30%, 50%,and 90% in 68%, 51% and 15%, respectively(Alison HM).

In a trial of chemotherapy naive CRPC patients 28 of 42 patients (67%) had PSA declines of 50% or greater, and 38% had soft tissue mass partial responses and 59% went from unfavorable CTC levels at baseline to favorable levels with treatment, and median time to PSA progression was 229 days (Attard G et al).

Abiraterone, is a CYP17 inhibitor and when used with prednisone compared to placebo plus prednisone in men with metastatic castration resistant prostate cancer who had disease progression after docetaxel chemotherapy: was associated with a 35% reduction in the risk of death, with a median survival of 14.8 months versus 10.9 months among patients who received placebo plus prednisone.

Abiratone resulted in an improved prostate specific antigen response, and improved objective response on the bases of radiographic findings, longer time to disease progression, and a longer progression free survival on the basis of radiographic findings.

Has significant activity in docetaxel failed patients with hormonally refractive prostate cancer.

Prolongs overall survival in patients with metastatic castration resistant prostate cancer whose disease has progressed after docetaxel-based chemotherapy (Phase III COU-AA-301 trial).

CHAARTED study showed adding docetaxel to ADT extended overall survival by a median of 13.6 months, compared with ADT alone in metastatic prostate cancer.

In the COU-AA301 trial 1200 patients would castration resistant metastatic prostate cancer with previous exposure to chemotherapy received abiraterone plus prednisone versus placebo plus prednisone: A median of 14.8 month versus 10.9 months overall survival was noted for the abiraterone arm (Scher HL et al).

Use associated with reduction in circulating androgens and increases in mineralcorticoids.

Associated with hypertension and hypokalemia, and fluid retention, related to excess mineralcorticoids due to CYP17A inhibition.

Most common side effects are fatigue, joint swelling and discomfort, edema, hot flashes, diarrhea, vomiting, cough, hypertension, dyspnea, hypokalemia, urinary tract infection, and bruising.

Should be used with caution in patients with CHF.

Effects of exposure may increase 10 fold when taken with meals.

Drug should be taken in in a non-fed state.

Can affect CYP enzymes, so drug interactions should be checked.

Blood pressure, signs of fluid retention, electrolyte and hepatic function should be monitored.

Most common side effects are largely abrogated by administration of low dose glucocorticoids.

Does not cause adrenal insufficiency.

Up-regulates in response to low levels of cortisol induced by abiraterone.

Requires concurrent use of low dose prednisone.

In the study of 56 men with localized high-risk prostate cancer defined as Gleason score = or > than eight, PSA = or > 20 mg/mL, T3 or T4 bulky disease, a high PSA velocity score, slightly more than one-third of patients had lymph node involvement: patients were treated with either 3-6 months of preoperative leuprolide or abiraterone, leuprolide and low-dose prednisone and then had biopsy of the prostate: a pathological complete response was observed in 10% of those treated with six months of combination therapy versus 4% in those with three months of combination therapy and near pathologic complete response was 24% versus 11%, respectively.

The above study suggests neoadjuvant therapy can make cancer disappear in a percentage of high-risk patients.

In the STAMPEDE and Latitude trials the addition of abiratone and prednisone to androgen deprivation therapy for newly diagnosed metastatic castration sensitive prostate cancer patients reducing risk of death by nearly 40%.

In the LATITUDE study 1,199 patients study randomized to abiraterone plus prednisone or placebo in patients that had received a gonadotropin releasing hormone analog or had bilateral orchiecty: reduced risk of death by 38%, increased median survival, delayed time to initiation of chemotherapy

Dose 1000 mg orally once daily, and use of concomitant prednisone.

Abiraterone is associated with greater risk of cardiovascular-related hospitalizations among men with prostate cancer than enzalutamide.

The incidence of cardiovascular-related hospitalizations were 10 events per 100 person-years for the abiraterone group vs 7 events per 100 person-years for the enzalutamide group.


Phase 3 ACIS trial, which compared radiographic progression-free survival of apalutamide vs placebo in combination with abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer (CRPC).

Trying to determine whether combining two androgen receptor inhibitor agents together, one that diminishes testosterone production and one that targets the androgen receptor would lead to better outcome than one agent alone.

The combination reduced the risks of progression by 31%.

A 7.4 months improvement in radiographic progression-free survival.

PSA declines reaching to undetectable levels of below 0.2, which was statistically improved with the combination over abiraterone alone.

Patients with visceral disease, either lung, liver, or adrenal, seemed to have even more benefit, in terms of radiographic progression‑free survival and overall survival.

In patients over 75 years old, this improvement in overall survival turned out to be statistically significant by reducing the risk of death by 25%.

The overall findings of the ACIS trial: the combination of abiraterone-prednisone plus apalutamide might improve the primary endpoint of radiographic progression free survival, but did not improve the secondary endpoints of overall survival, time to initiation of cytotoxic chemotherapy, time to chronic opioid use, or time to pain progression.

Leave a Reply

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