Abiraterone Oral
Abiraterone acetate is a prodrug of abiraterone, a potent, selective, and irreversible inhibitor of cytochrome P-450 (CYP) 17α-hydroxylase/C17,20-lyase (also referred to as CYP17); abiraterone is an antineoplastic agent.[1][5][6][10][13][28]
Brand Name: Zytiga
Class: Antineoplastic Agents (10:00)
Table of Contents
Uses
Prostate Cancer
Metastatic Castration-resistant Prostate Cancer
Abiraterone acetate is commercially available as conventional tablets (Zytiga®) and micronized tablets (Yonsa®).[1][28] Abiraterone acetate (conventional) is used in combination with prednisone and abiraterone acetate (micronized) is used in combination with methylprednisolone for the treatment of metastatic castration-resistant prostate cancer.[1][4][18][20][21][22][25][28][29][30]
Clinical Experience
Efficacy and safety of abiraterone conventional tablets are based principally on the results of 2 randomized, double-blind, placebo-controlled phase 3 studies (COU-AA-301 and COU-AA-302) in patients with metastatic castration-resistant prostate cancer.[1][4][18][20][21][22][25][28][30] Efficacy and safety of abiraterone acetate micronized tablets for the treatment of metastatic castration-resistant prostate cancer are based on the results of the COU-AA-301 and COU-AA-302 studies.[28][30] Although systemic exposure of abiraterone and suppression of testosterone concentration are similar between abiraterone acetate conventional and micronized tablets at equivalent dosages in patients with metastatic castration-resistant prostate cancer,[29][35] these formulations are not interchangeable due to differences in dosage, indication, and food effects.[28]
In the COU-AA-301 study, 1195 patients with metastatic castration-resistant prostate cancer that had progressed following treatment with 1 or 2 cytotoxic regimens, one of which had to contain docetaxel,[1][3][4][16] were randomized in a 2:1 ratio to receive either conventional abiraterone acetate tablets (1 g once daily) in combination with prednisone (5 mg twice daily) or placebo in combination with prednisone (5 mg twice daily).[1][3][4] Treatment was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.[1][3][4] Patients who previously received ketoconazole for treatment of prostate cancer were excluded from the study.[1][4] The primary measure of efficacy was overall survival.[4] The median age of patients enrolled in the study was 69 years.[1][4] Most of the patients (70%) had received one prior cytotoxic regimen.[1][3][4]
A planned interim analysis of the COU-AA-301 study indicated that patients receiving abiraterone acetate plus prednisone had a longer median overall survival (14.8 versus 10.9 months) than those receiving placebo plus prednisone.[1][3][4] The median follow-up at the time of the interim analysis was 12.8 months, and the median duration of treatment was 8 months for patients receiving abiraterone acetate and prednisone and 4 months for those receiving placebo and prednisone.[4] Because of the survival benefit observed at the interim analysis, study investigators permitted patients previously randomized to receive placebo to cross over to open-label abiraterone acetate therapy.[4]
Updated analysis of the COU-AA-301 study (performed when 97% of the planned number of deaths for final analysis had occurred) confirmed that patients receiving abiraterone acetate plus prednisone had a longer median overall survival (15.8 months) than those who received placebo plus prednisone (11.2 months).[1][3][25] At the final analysis, patients receiving abiraterone acetate and prednisone also had higher objective response rates (14.8 versus 3.3%) and prostate specific antigen (PSA) response rates (29.5 versus 5.5%), longer times to PSA progression (8.5 versus 6.6 months), and longer median progression-free survival based on radiographic evidence (5.6 versus 3.6 months) compared with those receiving placebo and prednisone.[25]
Results of a subgroup analysis of the COU-AA-301 study (based on age, geographic region, ECOG performance status, Brief Pain Inventory-Short Form [BPI-SF] score, number of prior chemotherapy regimens, PSA or radiographic progression, presence of visceral metastases, baseline PSA, LDH, and alkaline phosphatase concentrations) suggested that the effect of abiraterone acetate and prednisone on overall survival was consistent across all subgroups.[25] Exploratory analysis in patients with clinically important pain at baseline also suggested that abiraterone acetate and prednisone substantially improved palliation of pain (45 versus 28.8%) and reduced median time to palliation (5.6 versus 13.7 months) compared with those receiving placebo and prednisone.[26]
In the COU-AA-302 study, 1088 patients with chemotherapy-naive metastatic castration-resistant prostate cancer were randomized in a 1:1 ratio to receive either conventional abiraterone acetate tablets (1 g once daily) in combination with prednisone (5 mg twice daily) or placebo in combination with prednisone (5 mg twice daily).[1][20][22] Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.[1] Patients experiencing moderate or severe pain or cancer-related pain requiring treatment with opiate analgesics, those with visceral metastases, and those who previously received ketoconazole for more than 7 days were excluded from the study.[1] The primary measures of efficacy were overall survival and progression-free survival based on radiographic evidence (as evaluated by an independent review committee according to Prostate Cancer Clinical Trials Working Group-2 [PCCTWG-2] criteria for bone lesions and/or Response Evaluation Criteria in Solid Tumors [RECIST] for soft tissue lesions).[1][20] The median age of patients enrolled in the study was 70 years.[1] Most of the patients (66%) enrolled in the study indicated no pain (defined as a BPI-SF score of 0-1) and 26% reported mild pain (BPI-SF score of 2-3) during a 24-hour period at baseline.[1] All patients enrolled in the study had an ECOG performance status of 0 or 1.[1]
At the time of the final analysis for overall survival in the COU-AA-302 study (at a median follow-up of 49 months), patients receiving abiraterone acetate and prednisone had a longer median overall survival (34.7 versus 30.3 months) than those receiving placebo and prednisone.[1][22] Most patients (65% of those receiving abiraterone acetate and prednisone and 78% of those receiving placebo and prednisone) had received subsequent cytotoxic therapy associated with overall survival benefit in metastatic castration-resistant prostate cancer; 44 or 13% of patients randomized to receive placebo and prednisone or abiraterone acetate and prednisone, respectively, received subsequent abiraterone acetate therapy.[1][22] A planned interim analysis for progression-free survival indicated that patients receiving abiraterone acetate and prednisone had substantially prolonged progression-free survival based on radiographic evidence (hazard ratio: 0.43) compared with those receiving placebo and prednisone.[1] Abiraterone acetate and prednisone also prolonged the median time to initiation of cytotoxic therapy (25.2 versus 16.8 months) and delayed initiation of opiate analgesics for cancer-related pain (hazard ratio: 0.69) compared with placebo and prednisone.[1]
Results of a subgroup analysis of the COU-AA-302 study (based on age, ECOG performance status, BPI-SF score, presence of bone metastases, geographic region, and baseline PSA, LDH, and alkaline phosphatase concentrations) suggested that the effect of abiraterone acetate and prednisone on overall survival was generally consistent across all subgroups; however, combination therapy with abiraterone acetate and prednisone had a greater effect on overall survival relative to placebo and prednisone in patients with no pain at baseline than in those with mild pain at baseline (hazard ratio: 0.77 and 0.97, respectively).[22]
Metastatic Castration-sensitive Prostate Cancer
Abiraterone acetate (conventional tablets) is used in combination with prednisone for the treatment of high-risk metastatic castration-sensitive prostate cancer;[1][23][24] the drug also has been used in combination with prednisolone† .[31][32][33] The current indication is based on substantially prolonged overall survival compared with placebo in men with metastatic castration-sensitive prostate cancer and at least 2 high-risk factors associated with poor prognosis.[1]
The micronized formulation of abiraterone acetate is not currently FDA-labeled for use in patients with metastatic castration-sensitive prostate cancer.[28]
Clinical Experience
The current indication for abiraterone acetate (conventional tablets) in patients with high-risk metastatic castration-sensitive prostate cancer is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (LATITUDE).[1][23][24] Patients enrolled in the study must have had at least 2 of the following high-risk factors associated with poor prognosis: total Gleason score of 8 or more, presence of at least 3 bone lesions, or presence of measurable visceral metastases.[1][23] Patients with substantial cardiac, adrenal, or hepatic dysfunction were excluded from the study.[1] In this study, 1199 patients were randomized in a 1:1 ratio to receive conventional abiraterone acetate tablets (1 g once daily) in combination with prednisone (5 mg once daily) or placebo; all patients enrolled in the study received androgen deprivation therapy.[1][23] Treatment was continued until disease progression, death, or unacceptable toxicity occurred or the patient withdrew from the study.[1] The primary measures of efficacy were overall survival and progression-free survival based on radiographic evidence (as evaluated by an independent review committee according to PCCTWG-2 criteria for bone lesions and/or RECIST for soft tissue lesions).[1][23] The median age of patients enrolled in the study was 67 years and 97% of patients had an ECOG performance status of 0 or 1.[1] One-half of the patients enrolled in the study indicated no pain (defined as a BPI-SF score of 0-1), 23% reported mild pain (BPI-SF score of 2-3), and 28% reported moderate or severe pain (BPI-SF score of 4 or more) during a 24-hour period at baseline.[1]
At a median follow-up of 30.4 months, median overall survival had not been reached in patients receiving abiraterone acetate and prednisone and was 34.7 months in those receiving placebo; however, abiraterone acetate and prednisone reduced the risk of death by 38% compared with placebo.[1][23] Progression-free survival based on radiographic evidence was substantially prolonged in patients receiving abiraterone acetate and prednisone compared with those receiving placebo (33 versus 14.8 months; hazard ratio for radiographic progression or death: 0.47).[23] The median duration of treatment was 24 months for patients receiving abiraterone acetate and prednisone and 14 months for those receiving placebo.[23] Because of the survival benefit observed at the interim analysis, an independent data monitoring committee recommended that patients previously randomized to receive placebo cross over to open-label abiraterone acetate therapy.[23] An updated overall survival analysis at a median follow-up of 52 months confirmed prolonged median overall survival (53.3 versus 36.5 months; hazard ratio for death: 0.66) in patients receiving abiraterone acetate and prednisone compared with those receiving placebo.[1][24] Abiraterone acetate and prednisone substantially delayed the time to initiation of cytotoxic therapy compared with placebo.[1] At the time of the updated analysis, 29% of patients receiving abiraterone acetate and prednisone and 45% of placebo recipients had received subsequent therapy associated with overall survival benefit in metastatic castration-resistant prostate cancer.[1]
Results of a subgroup analysis of the LATITUDE study (based on age, ECOG performance status, geographic region, bone lesion size, presence of visceral metastases, and baseline PSA and LDH concentrations) suggested that the effect of abiraterone acetate and prednisone on overall survival was consistent in most subgroups, except for those with an ECOG performance status of 2 or a Gleason score of less than 8.[24]
Clinical Perspective
The American Society of Clinical Oncology (ASCO) developed clinical practice guidelines for the treatment of metastatic noncastrate (also referred to as androgen-sensitive) prostate cancer.[33] Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy, represent four separate standards of care for noncastrate metastatic prostate cancer.[33] ASCO does not make any specific recommendations for the use of any of these agents in any particular combination or in any particular series.[33] ASCO states that the addition of abiraterone to androgen deprivation therapy should be offered to men with high-risk de novo metastatic noncastrate prostate cancer; the recommended regimen is abiraterone (conventional formulation) in combination with either prednisone or prednisolone† .[33]
Nonmetastatic Castration-sensitive Prostate Cancer
In 2021, the American Society of Clinical Oncology (ASCO) released a guideline update regarding the initial management ofcastration-sensitive (noncastrate) advanced, recurrent, or metastatic prostate cancer.† [33] An Expert Panel evaluated the clinical data of combination therapies as compared to castration alone for men with castration-sensitive locally advanced nonmetastatic prostate cancer.[33] The Panel concluded that abiraterone in combination with prednisolone and androgen deprivation therapy (ADT) should be considered for men with castration-sensitive, locally advanced, nonmetastatic prostate cancer, versus castration monotherapy, based on results from the STAMPEDE trial.[33]
The STAMPEDE investigators utilized a multigroup, multistage platform design to investigate if the earlier administration of abiraterone in men on long-term ADT (orchiectomy or gonadotropin-releasing hormone [GnRH] agonists or antagonists) could improve survival.[10002] Men included in this study (N=1917) had prostate cancer that was newly diagnosed and metastatic, node-positive, or high-risk locally advanced or disease that was treated prior with radical surgery or radiotherapy and was currently relapsing with high-risk features (in men no longer receiving therapy, a prostate specific antigen [PSA] >4 ng/mL with a doubling time of <6 months, a PSA >20 ng/mL, nodal or metastatic relapse, or <12 months of total ADT with an interval of >12 months without treatment).[10002] Men with clinically significant cardiovascular disease were excluded from the study.[10002] Patients were randomly assigned in an open-label fashion to ADT alone (n=957) or ADT in combination with abiraterone 1000 mg and prednisolone 5 mg once daily (n=960).[10002] Of these, 915 patients had advanced prostate cancer and no metastases; 455 were randomly assigned to ADT alone and 460 to ADT plus abiraterone and prednisolone.[10002]
Androgen deprivation therapy was administered for at least 2 years.[10002] Patients with node-negative, nonmetastatic disease were required to undergo local radiotherapy at 6 to 9 months post-randomization while those with positive nodes were encouraged to receive such therapy.[10002] For patients with nonmetastatic disease with radiotherapy planned, treatment was to continue for 2 years or until any type of disease progression, whichever occurred first.[10002] For patients with nonmetastatic disease with no radiotherapy or those with metastatic disease, treatment continued until PSA, radiologic, or clinical progression or until another therapy was initiated.[10002] The primary outcome was overall survival, defined as time from randomization to death from any cause.[10002] The intermediate primary outcome was failure-free survival, defined as the time to the earliest of biochemical failure, disease progression, or death.[10002]
The median age of patients in the ADT monotherapy and combination therapy groups was 67 years.[10002] Seventy-eight percent of patients in each group had a World Health Organization (WHO) performance status of 0, with the remaining 22% of patients in each group having a WHO performance status of 1 or 2.[10002] In the ADT monotherapy group, 27% of patients had newly diagnosed, node-negative, nonmetastatic disease; 20% had newly diagnosed, node-positive, nonmetastatic disease; and 1% had previously treated nonmetastatic disease.[10002] In the combination therapy group, the percentages for these groups were 26%, 19%, and 3%, respectively.[10002] The remaining patients in either group had newly diagnosed or previously treated metastatic disease.[10002]
Results revealed a significant improvement in overall survival (for patients with metastatic and nonmetastatic disease) with combination therapy as compared to ADT alone at a median follow-up of 40 months; 184 deaths in the combination group versus 262 in the monotherapy group.[10002] The 3-year overall survival rate was 83% in the combination group versus 76% in the monotherapy group.[10002] A subgroup analysis of overall survival among men with nonmetastatic disease was premature as few patients died by the study publication date.[33][10002] Failure-free survival was significantly improved for patients with nonmetastatic disease treated with ADT plus abiraterone and prednisolone compared with those treated with ADT alone.[33] Combination therapy was associated with a 79% relative improvement in this outcome, although treatment duration was 2 years or less.[33][10002] Regarding safety, grade 3 to 5 adverse events occurred more frequently in patients in the combination group as compared to the ADT alone group (47% versus 33%).[10002]
The prior clinical study was also included in a meta-analysis of primary results from 2 randomized, controlled, phase 3 trials of the STAMPEDE platform protocol that included patients with high-risk, or relapsing with high-risk features, nonmetastatic prostate cancer and a WHO performance status of 0-2.[10003] The other included trial compared ADT with ADT plus enzalutamide 160 mg once daily, abiraterone, and prednisolone (same doses as above STAMPEDE trial).[10003] A total of 1974 nonmetastatic patients were randomly assigned in both trials to standard of care (control) or with combination therapy.[10003] The primary endpoint was metastasis-free survival, defined as time from randomization to death from any cause or to distant metastases confirmed by imaging.[10003]
Overall, there were 180 metastasis-free survival events in the combination therapy groups and 306 in the control groups with a median follow-up of 72 months.[10003] Results revealed that metastasis-free survival was significantly longer in the combination therapy groups as compared to the control groups, with 6-year metastasis-free survival improved from 69% (control) to 82% (combination therapy).[10003] There was no evidence of a difference in metastasis-free survival when comparing concurrent administration of abiraterone and enzalutamide to abiraterone alone.[10003] Secondary endpoints, including overall survival, prostate-cancer specific survival, biochemical failure-free-survival, and progression-free survival were also significantly longer in the combination therapy versus control groups.[10003]
Based on current evidence, abiraterone plus prednisolone and ADT for the treatment of nonmetastatic castration-sensitive prostate cancer has Level 2 (moderate strength/quality) evidence supporting its use.[33][10002] Currently available data include results from a multigroup, multistage platform design study with randomization and an open-label treatment approach.[33][10002][10003] Based on these data, abiraterone plus prednisolone and ADT should be considered for men with nonmetastatic, castration-sensitive, locally advanced prostate cancer.[33] Nonmetastatic patients with node-positive disease should also receive radiotherapy and those without lymph node involvement should have high-risk features as noted in the STAMPEDE trial in order to receive abiraterone combination therapy.[10002]
Dosage And Administration
General
Pretreatment Screening
Obtain baseline serum ALT, AST, and bilirubin concentrations.[1][28]Assess blood pressure prior to initiation of abiraterone; blood pressure must be controlled prior to initiation of the drug.[1][28]Assess serum potassium concentration; correct hypokalemia prior to initiation of the drug.[1][28]
Patient Monitoring
Monitor serum ALT, AST, and bilirubin concentrations every 2 weeks for the first 3 months of therapy and monthly thereafter; in patients with preexisting moderate hepatic impairment, monitor serum ALT, AST, and bilirubin concentrations every week for the first month of therapy, every 2 weeks for the following 2 months of therapy, and then monthly thereafter.[1][28]In patients who develop hepatotoxicity during abiraterone therapy and resume treatment with the drug, serum ALT, AST, and bilirubin concentrations should be monitored at a minimum of every 2 weeks for the first 3 months and then monthly thereafter.[1][28]Monitor blood pressure, serum potassium concentration, and fluid status monthly.[1][28] More frequent monitoring may be necessary in patients with a history of cardiovascular disease or other cardiac-related comorbidities.[1][28]Monitor for signs and symptoms of adrenocortical insufficiency.[1][28]Monitor blood glucose concentrations in patients with diabetes mellitus.[1][28]
Dispensing and Administration Precautions
Abiraterone acetate is commercially available as conventional tablets (Zytiga®) and micronized tablets (Yonsa®); these formulations are not interchangeable due to differences in dosage, indication, and food effects.[1][28]
Handling and DisposalFemales who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).[1][28]
Other General Considerations
Use concurrently with a gonadotropin-releasing hormone (GnRH) analog unless the patient has undergone bilateral orchiectomy.[1][28]
Administration
Conventional abiraterone acetate tablets should be administered orally on an empty stomach; no food should be consumed for at least 2 hours before or 1 hour after a dose.[1][18] Because of normal variations in the content and composition of meals, administration of abiraterone acetate conventional tablets with food is likely to result in highly variable exposure to the drug.[1]
The bioavailability of the micronized formulation of abiraterone acetate is less variable compared with the conventional formulation; therefore, the micronized formulation may be administered without regard to food.[28][30]
Conventional and micronized tablets should be swallowed whole with water and should not be chewed or crushed.[1][28]
Dosage
Prostate Cancer
Metastatic Castration-resistant Prostate Cancer
Conventional tablets: For the treatment of castration-resistant metastatic prostate cancer, the recommended dosage of abiraterone acetate (conventional) is 1 g once daily in combination with prednisone 5 mg orally twice daily.[1][4]
Micronized tablets: For the treatment of castration-resistant metastatic prostate cancer, the recommended dosage of abiraterone acetate (micronized) is 500 mg once daily in combination with methylprednisolone 4 mg orally twice daily.[28]
Metastatic Castration-sensitive Prostate Cancer
Conventional tablets: For the treatment of high-risk castration-sensitive metastatic prostate cancer, the recommended dosage of abiraterone acetate (conventional tablets) is 1 g once daily in combination with prednisone 5 mg orally once daily.[1]
Nonmetastatic Castration-sensitive Prostate Cancer
When abiraterone is used in combination with prednisolone and androgen deprivation therapy (ADT) for the treatment of nonmetastatic castration-sensitive prostate cancer† , the usual dosage administered in clinical studies is 1000 mg orally once daily.[33][10002]
Dosage Modification
Hepatotoxicity
In patients who exhibit substantial increases in serum aminotransferase concentrations (ALT and/or AST exceeding 5 times the upper limit of normal [ULN]) or total bilirubin concentrations (exceeding 3 times the ULN), therapy with abiraterone acetate should be withheld until liver function test results return to baseline values or until ALT and AST decrease to no more than 2.5 times the ULN and total bilirubin concentrations decrease to no more than 1.5 times the ULN.[1][28] Abiraterone acetate therapy may then be resumed at a reduced dosage of 750 mg once daily (conventional abiraterone) or 375 mg once daily (micronized abiraterone) with monitoring of serum aminotransferase and bilirubin concentrations at least every 2 weeks for 3 months and monthly thereafter.[1][28]
If hepatotoxicity recurs at a dosage of 750 mg once daily (conventional abiraterone) or 375 mg once daily (micronized abiraterone), therapy should be withheld again until liver function test results return to baseline values or until ALT and AST concentrations decrease to no more than 2.5 times the ULN and total bilirubin concentrations decrease to no more than 1.5 times the ULN; therapy may then be resumed at a reduced dosage of 500 mg once daily (conventional abiraterone) or 250 mg once daily (micronized abiraterone).[1][28]
If hepatotoxicity recurs at a dosage of 500 mg once daily (conventional abiraterone) or 250 mg once daily (micronized abiraterone), treatment with abiraterone acetate should be discontinued.[1][28]
In patients who exhibit elevations in ALT concentrations exceeding 3 times the ULN and total bilirubin concentrations exceeding 2 times the ULN in the absence of biliary obstruction or other causes, treatment with abiraterone acetate should be permanently discontinued.[1][28]
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of abiraterone with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided.[1] If concomitant use cannot be avoided, the frequency of abiraterone acetate dosing should be increased from once daily to twice daily (e.g., from 1 g once daily to 1 g twice daily [conventional abiraterone] or from 500 mg once daily to 500 mg twice daily [micronized abiraterone]).[1][28] When concomitant use of the potent CYP3A4 inducer is discontinued, the prior dose and frequency of abiraterone acetate should be resumed.[1][28]
Special Populations
Hepatic Impairment
Use of abiraterone in patients with severe preexisting hepatic impairment (Child-Pugh class C) is not recommended.[1][28]
For patients with moderate preexisting hepatic impairment (Child-Pugh class B), the manufacturer recommends an abiraterone acetate dosage of 250 mg once daily (conventional abiraterone) or 125 mg once daily (micronized abiraterone) with monitoring of serum aminotransferase and bilirubin concentrations prior to initiation of therapy, every week for the first month of therapy, every 2 weeks during the second and third months of therapy, and then monthly thereafter.[1][28] Abiraterone acetate should be permanently discontinued in patients with moderate preexisting hepatic impairment if aminotransferase concentrations (ALT and/or AST) increase above 5 times the ULN or total bilirubin concentrations increase above 3 times the ULN.[1][28]
Dosage adjustment is not necessary in patients with mild preexisting hepatic impairment.[1][28]
Renal Impairment
No dosage adjustment is necessary in patients with renal impairment.[1][28]
Geriatric Patients
The manufacturer makes no specific dosage recommendations for geriatric patients.[1][28]
Cautions
Contraindications
Warnings/Precautions
Excessive Mineralocorticoid Activity
Inhibition of the 17α-hydroxylase enzyme (also referred to as CYP17) results in decreased serum concentrations of cortisol, which leads to stimulation of corticotropin (ACTH) release and a resultant increase in steroids with mineralocorticoid activity upstream of the enzyme blockade.[8][10][12] This secondary mineralocorticoid excess commonly is manifested as hypertension, hypokalemia, and fluid retention.[1][9][10][14][28] The severity and incidence of these mineralocorticoid effects may be reduced by concomitant administration of a glucocorticoid to suppress ACTH release and steroid synthesis upstream of the CYP17 blockade.[5][7][8][9][10][12][14]
In a combined safety database of 4 placebo-controlled studies evaluating abiraterone acetate (conventional) in combination with prednisone twice daily, grade 3-4 hypokalemia was reported in 4 or 2% of abiraterone- or placebo-treated patients, respectively.[1] In these studies, the incidence of grade 3-4 hypertension (2%) or grade 3-4 edema (1%) was similar in both treatment groups.[1] In the LATITUDE study evaluating abiraterone acetate (conventional) in combination with prednisone once daily, grade 3-4 hypokalemia (10 versus 1%) or grade 3-4 hypertension (20 versus 10%) was reported more frequently in patients receiving abiraterone acetate compared with those receiving placebo, but the incidence of grade 3-4 edema was similar in both treatment groups (1%).[1] Prolongation of the QT interval and torsades de pointes also have been reported during postmarketing experience with abiraterone acetate in patients who developed hypokalemia during therapy.[1][28]
Patients with a history of cardiovascular disease or with any underlying medical condition that might be compromised by increases in blood pressure, hypokalemia, or fluid retention (e.g., heart failure, recent myocardial infarction, ventricular arrhythmia) should be closely monitored.[1][28] Patients with a left ventricular ejection fraction of less than 50% or with New York Heart Association (NYHA) class II, III-IV heart failure were excluded from phase 3 clinical studies evaluating abiraterone in patients with metastatic prostate cancer; therefore, safety of the drug in such patients has not been established.[1][28] Patients should be monitored at least monthly for hypertension, hypokalemia, and fluid retention.[1][28] Blood pressure should be controlled and hypokalemia should be corrected before and during treatment.[1][28]
Adrenocortical Insufficiency
In a combined safety database of 5 randomized, placebo-controlled studies, adrenocortical insufficiency was reported in 0.3% of 2230 patients receiving abiraterone acetate (conventional) compared with 0.1% of 1763 patients receiving placebo.[1] In patients receiving abiraterone acetate (conventional) in combination with prednisone, adrenocortical insufficiency has been reported following interruption of the daily corticosteroid regimen and/or during periods of infection or stress.[1][28]
Patients should be monitored for manifestations of adrenocortical insufficiency, especially following dosage reduction or discontinuance of corticosteroids or when the patient is subjected to unusual stress.[1][28] An increase in corticosteroid dosage before, during, and after stressful situations may be indicated.[1][28] Manifestations of adrenocortical insufficiency may be masked by symptoms of mineralocorticoid excess; if clinically indicated, appropriate tests should be performed to confirm the diagnosis of adrenocortical insufficiency.[1][28]
Hepatic Toxicity
In a combined safety database of 5 randomized, placebo-controlled studies, grade 3-4 elevations in aminotransferase (ALT or AST) concentrations exceeding 5 times the upper limit of normal (ULN) occurred in 6% of 2230 patients receiving abiraterone acetate (conventional), generally during the initial 3 months of therapy.[1] In these studies, elevations in liver function test results were reported more frequently in patients with preexisting ALT or AST elevations than in patients with normal baseline aminotransferase concentrations.[1] Discontinuance of abiraterone acetate was necessary because of hepatic dysfunction (e.g., elevated aminotransferase concentrations) in 1.1% of 2230 patients receiving the drug.[1] In these studies, no fatalities were reported because of hepatic toxicity in abiraterone-treated patients.[1] Fulminant hepatitis, acute liver failure, and death associated with abiraterone acetate have been reported in postmarketing experience.[1][28]
Serum ALT, AST, and bilirubin concentrations should be evaluated prior to initiation of therapy and monitored every 2 weeks for the first 3 months of therapy and then monthly thereafter.[1][28] For patients with moderate preexisting hepatic impairment, serum aminotransferase and bilirubin concentrations should be evaluated prior to initiation of therapy and monitored every week for the first month of therapy, every 2 weeks during the second and third months of therapy, and then monthly thereafter.[1][28] More frequent monitoring is indicated if aminotransferase or bilirubin concentrations rise above pretreatment levels.[1][28] If manifestations suggestive of hepatotoxicity develop, liver function tests should be evaluated promptly.[1][28] If ALT and/or AST elevations exceed 5 times the ULN or total bilirubin elevations exceed 3 times the ULN, treatment should be interrupted and hepatic function monitored closely.[1][28] Therapy with the drug should be reinitiated at a reduced dosage only after liver function test results have returned to baseline values or after ALT and AST have decreased to no more than 2.5 times the ULN and total bilirubin concentrations have decreased to no more than 1.5 times the ULN.[1][28] If elevations in ALT concentrations exceeding 3 times the ULN and total bilirubin concentrations exceeding 2 times the ULN occur in the absence of biliary obstruction or other causes, abiraterone therapy should be permanently discontinued.[1][28]
Treatment-related Mortality and Fractures
Increased mortality and fractures have been reported in a clinical trial in patients receiving abiraterone acetate (conventional) in combination with a corticosteroid and radium Ra 223 dichloride for asymptomatic or mildly symptomatic castration-resistant prostate cancer metastatic to bone.[1][28] Abiraterone acetate is not currently FDA-labeled for use in combination with prednisone (or prednisolone) and radium Ra 223 dichloride.[1][28] At the time of the initial analysis in a randomized, placebo-controlled clinical trial (ERA-223) enrolling 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer metastatic to bone, fractures (28.6 versus 11.4%) and death (38.5 versus 35.5%) occurred more frequently in patients receiving abiraterone acetate in combination with prednisone (or prednisolone) and radium Ra 223 dichloride compared with those receiving abiraterone acetate in combination with prednisone (or prednisolone).[1][28] Based on recommendations from an independent data monitoring board, the treatment groups were unblinded.[1][28]
The manufacturers of abiraterone acetate state that use of radium Ra 223 dichloride in combination with the conventional formulation of the drug and prednisone (or prednisolone) or the micronized formulation of the drug and methylprednisolone is not recommended outside of a clinical trial.[1][28]
Fetal/Neonatal Morbidity and Mortality
Abiraterone may cause fetal harm and loss of pregnancy based on its mechanism of action and animal findings; the drug has been shown to be embryofetotoxic and teratogenic in animals.[1][28] Safety and efficacy of abiraterone have not been established in females.[1][28] Reproduction studies in rats revealed embryofetal lethality, bilateral ureter dilation, decreased anogenital distance, and decreased fetal body weight at exposure levels 0.03 or more times the human exposure.[1][28] Patients receiving abiraterone should be apprised of the potential fetal hazard and the potential risk for loss of pregnancy.[1][28]
Females who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).[1][28]
Males receiving the drug should use an effective contraceptive method during sexual encounters with females of reproductive potential.[1][28] These contraceptive measures are required during and for 3 weeks following discontinuance of abiraterone therapy.[1][28]
Infertility
Results of animal studies suggest that abiraterone acetate may impair male fertility.[1][28] In a general toxicology study, atrophy or hyperplasia of reproductive tissues and aspermia/hypospermia were observed in male rats receiving abiraterone at exposure levels similar to the human exposure at the recommended dosage.[1][28] In a fertility study, reduced reproductive organ weights and abnormal sperm count, motility, and morphology were observed in male rats receiving abiraterone at a dosage of 30 mg/kg or more daily; the effects of abiraterone on fertility appeared to be reversible 16 weeks after discontinuance of the drug.[1][28] Increased preimplantation embryonic loss and reduced number of corpora lutea, implantations, and live embryos were observed in untreated female rats mated to abiraterone-treated male rats.[1][28]
Hypoglycemia
Abiraterone acetate may cause severe hypoglycemia in patients with preexisting diabetes mellitus receiving repaglinide or thiazolidinedione-containing medications (e.g., pioglitazone).[1][28] Blood glucose concentrations should be monitored in patients with diabetes mellitus during and after discontinuation of abiraterone therapy, and antihyperglycemic drug therapy should be adjusted as indicated to decrease the risk of hypoglycemia.[1][28]
Specific Populations
Pregnancy
Based on its mechanism of action and animal findings, abiraterone can cause fetal harm and potential loss of pregnancy if administered to pregnant women.[1][28]
Lactation
Safety and efficacy of abiraterone have not been established in females.[1][28] It is not known whether abiraterone is distributed into milk in humans.[1][28] The effects of the drug on the breast-fed infant or milk production also are not known.[1][28]
Pediatric Use
Safety and efficacy have not been established in pediatric patients.[1][28]
Geriatric Use
In clinical trials evaluating abiraterone acetate (conventional), 70% of patients were 65 years of age or older and 27% were 75 years of age or older.[1] No overall differences in safety and efficacy were observed between geriatric patients and younger adults.[1][27][28] However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.[1][28]
Hepatic Impairment
Systemic exposure of abiraterone is increased by approximately 1.1- or 3.6-fold and the mean half-life of the drug is prolonged to approximately 18 or 19 hours in patients with preexisting mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, respectively, compared with individuals with normal hepatic function.[1][28] Dosage adjustment and careful monitoring of hepatic function are required in patients with moderate hepatic impairment.[1][28]
Systemic exposure of abiraterone is increased by approximately sevenfold in patients with preexisting severe hepatic impairment (Child-Pugh class C) compared with individuals with normal hepatic function.[1][28] Decreased protein binding of the drug resulting in a twofold increase in the free fraction of abiraterone also was observed in patients with severe hepatic impairment compared with individuals with normal hepatic function.[1][28] Use of abiraterone acetate in patients with severe preexisting hepatic impairment is not recommended.[1][28]
Renal Impairment
Following oral administration of a single 1-g dose of abiraterone acetate (conventional), pharmacokinetic values in patients with end-stage renal disease requiring hemodialysis were similar to those in individuals with normal renal function; no dosage adjustment is required in patients with renal impairment.[1][28]
Common Adverse Effects
Adverse effects reported in 10% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (twice daily) for the treatment of metastatic castration-resistant prostate cancer and at an incidence that is at least 2% higher than that reported with placebo and prednisone in the COU-AA-301 or COU-AA-302 studies include fatigue,[1] joint swelling or discomfort,[1] edema,[1][4] muscle discomfort,[1] constipation,[1] diarrhea,[1] hot flush,[1] hypertension,[1][4] cough,[1] insomnia,[1] contusion,[1] upper respiratory tract infection,[1] urinary tract infection,[1] dyspnea,[1] dyspepsia,[1] nasopharyngitis,[1] and hematuria.[1] Laboratory abnormalities reported in 20% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (twice daily) and at an incidence that is at least 2% higher than that reported with placebo include hypertriglyceridemia,[1] hyperglycemia,[1] elevated concentrations of aminotransferases (i.e., ALT, AST),[1] lymphopenia,[1] hypernatremia,[1] hypokalemia,[1] and hypophosphatemia.[1]
In the STAAR study, adverse effects reported in men with metastatic castration-resistant prostate cancer who received micronized abiraterone acetate were generally similar to adverse effects reported in those who received conventional abiraterone acetate.[29][30] One or more adverse effects were reported in 75% of patients who received micronized abiraterone acetate and in 83% of those who received conventional abiraterone acetate.[29][30]
Adverse effects reported in 10% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (once daily) for the treatment of high-risk metastatic castration-sensitive prostate cancer and at an incidence that is at least 2% higher than that reported with placebo in the LATITUDE study include hypertension,[1] hypokalemia,[1] lymphopenia,[1] elevated concentrations of aminotransferases (i.e., ALT, AST),[1] and hot flush.[1]
Drug Interactions
In vitro studies indicate that abiraterone has the potential to inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2D6, and 2C8 and, to a lesser extent, CYP isoenzymes 2C9, 2C19, and 3A4/5.[1][28] Abiraterone is a substrate of CYP3A4 in vitro.[1][28] In vitro studies indicate that neither abiraterone acetate nor abiraterone is a substrate of P-glycoprotein (P-gp) at clinically relevant concentrations; however, abiraterone acetate is an inhibitor of P-gp.[1][28] In vitro, abiraterone and its major metabolites are inhibitors of organic anion transport protein (OATP) 1B1.[1][28]
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant administration of abiraterone acetate (conventional abiraterone) with the potent CYP3A4 inhibitor ketoconazole did not result in clinically important changes in pharmacokinetics of abiraterone.[1][28]
Concomitant use of abiraterone acetate with potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may result in decreased plasma concentrations of abiraterone.[1][28] When the potent CYP3A4 inducer rifampin (600 mg daily for 6 days) was administered concomitantly with abiraterone acetate (single 1-g dose of conventional formulation), the mean systemic exposure of abiraterone was decreased by 55%.[1][28] Concomitant use of abiraterone acetate with potent inducers of CYP3A4 should be avoided.[1][28] If concomitant use cannot be avoided, the frequency of abiraterone acetate dosing should be increased from once daily to twice daily (e.g., from 1 g once daily to 1 g twice daily [conventional abiraterone]; from 500 mg once daily to 500 mg twice daily [micronized abiraterone]).[1][28] When concomitant use of the potent CYP3A4 inducer is discontinued, the prior dose and frequency of abiraterone acetate should be resumed.[1][28]
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of abiraterone acetate with CYP2D6 substrates may result in increased serum concentrations and possible toxicity of the CYP2D6 substrate drug.[1][18][28] When the CYP2D6 substrate dextromethorphan hydrobromide (single 30-mg dose) was administered concomitantly with abiraterone acetate (1 g daily of conventional formulation) and prednisone (5 mg twice daily), peak plasma concentration and systemic exposure of dextromethorphan were increased 2.8- and 2.9-fold, respectively.[1][2][28] Concomitant use of abiraterone acetate with CYP2D6 substrates that have a narrow therapeutic index (e.g., thioridazine) should be avoided.[1][15][28] If concomitant use cannot be avoided, reduction of the dosage of the CYP2D6 substrate drug should be considered, and the drugs should be used concomitantly with caution.[1][15][28]
Concomitant use of abiraterone acetate with CYP2C8 substrates may result in increased serum concentrations of the CYP2C8 substrate drug and possible toxicity.[1][28] When the CYP2C8 substrate pioglitazone was administered concomitantly with abiraterone acetate (single 1-g dose of conventional formulation), systemic exposure to pioglitazone was increased by 46%.[1][28] Severe hypoglycemia has been reported in patients with preexisting diabetes mellitus when abiraterone acetate was administered concomitantly with repaglinide or thiazolidinedione-containing medications (including pioglitazone).[1][28] If abiraterone acetate is used concomitantly with CYP2C8 substrates that have a narrow therapeutic index, patients should be closely monitored for signs of toxicity of the CYP2C8 substrate drug.[1][28]
When the CYP1A2 substrate theophylline (single 100-mg dose) was administered concomitantly with abiraterone acetate (1 g daily of conventional formulation) and prednisone (5 mg twice daily), systemic exposure of theophylline was unchanged.[1][28]
Description
Abiraterone acetate is a prodrug of abiraterone, a potent, selective, and irreversible inhibitor of cytochrome P-450 (CYP) 17α-hydroxylase/C17,20-lyase (also referred to as CYP17); abiraterone is an antineoplastic agent.[1][5][6][10][13][28] The CYP17 enzyme is expressed in the testes and adrenal glands, and also is expressed in prostatic tumor tissue.[1][6][10][12][28] CYP17 catalyzes 2 sequential reactions: 17α-hydroxylase catalyzes the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives, and C17,20-lyase catalyzes the conversion of these 17α-hydroxy derivatives to dehydroepiandrosterone (DHEA) and androstenedione.[1][6][10][12][28] DHEA and androstenedione are androgenic precursors of testosterone.[1][6][10][12][28] Testosterone and dihydrotestosterone bind to and activate the androgen receptor, which is key in the development and progression of prostate cancer.[10][11][12] Thus, inhibition of CYP17 activity by abiraterone results in suppression of androgen production.[10][12] Inhibition of CYP17 activity by abiraterone also can result in increased mineralocorticoid synthesis by the adrenal glands and subsequent risk of hypertension, hypokalemia, and fluid retention.[1][3][28] Abiraterone is tenfold to 30-fold more potent than ketoconazole (a nonspecific CYP inhibitor and weak inhibitor of CYP17) in its inhibition of the CYP17 enzyme.[5][9]
Although decreases in serum testosterone and other androgens have been observed with abiraterone acetate therapy for prostate cancer, it is not necessary to monitor the effect of abiraterone on serum testosterone levels.[1][28] Changes in serum prostate specific antigen (PSA) concentrations also may be observed, but have not been shown to correlate with clinical benefit in individual patients.[1][28]
Following oral administration, abiraterone acetate is hydrolyzed, most likely by esterases in non-CYP-dependent pathways, to its active metabolite, abiraterone.[1][28] Peak plasma concentrations of abiraterone occur 2 hours after administration of the parent drug.[1][28] Abiraterone is further metabolized to form 2 inactive sulfate conjugates, abiraterone sulfate (formed by SULT2A1, a sulfotransferase that catalyzes the sulfate conjugation of DHEA and other steroids) and N-oxide abiraterone sulfate (formed by CYP3A4 and SULT2A1).[1][19][28] The mean terminal half-life of abiraterone in patients with metastatic castration-resistant prostate cancer is 12 hours.[1][28] Following oral administration of a radiolabeled dose of abiraterone acetate, about 88% of the dose is recovered in feces, mainly as abiraterone acetate (55%) and abiraterone (22%), and 5% of the dose is recovered in urine.[1][28]
Systemic exposure to abiraterone is dose proportional over a dose range of 250 mg to 1 g (conventional abiraterone) and 125 mg to 625 mg (micronized abiraterone); however, systemic exposure to abiraterone did not substantially increase when the dose of the conventional formulation was doubled from 1 g to 2 g.[1][28]
Systemic exposure to abiraterone is increased when abiraterone acetate is administered with food.[1][8][13][28] Oral administration of a single 1-g dose of abiraterone acetate (conventional) with a low-fat or high-fat meal resulted in increases in systemic exposure of approximately fivefold or tenfold, respectively, and increases in peak plasma concentrations of approximately sevenfold or 17-fold, respectively, compared with administration in the fasted state.[1] When a single dose of abiraterone acetate (conventional) was administered 2 hours after or 1 hour before a medium-fat meal, systemic exposure of abiraterone increased approximately sevenfold or 1.6-fold, respectively, compared with administration in the fasted state.[1] In patients with metastatic castration-resistant prostate cancer, systemic exposure to abiraterone was similar following administration of abiraterone acetate (conventional) for 7 days with a low-fat meal or at least 2 hours after or 1 hour before a meal, but increased approximately twofold when administered with a high-fat meal.[1] Oral administration of a single 500-mg dose of abiraterone acetate (micronized) with a high-fat meal resulted in increases in systemic exposure and peak plasma concentrations of approximately 4.4-fold and 6.5-fold, respectively, compared with administration in the fasted state.[28] The bioavailability of the micronized formulation of abiraterone acetate is less variable compared with the conventional formulation; therefore, the micronized formulation may be administered without regard to food.[28][30] Conventional abiraterone acetate must be administered on an empty stomach; no food should be consumed for at least 2 hours before or 1 hour after a dose.[1]
Abiraterone is a potent inhibitor of CYP isoenzymes 1A2 and 2D6 and a moderate inhibitor of CYP isoenzymes 2C9, 2C19, and 3A4/5.[1][28] In vitro studies indicate that neither abiraterone acetate nor abiraterone is a substrate of P-glycoprotein (P-gp); however, abiraterone acetate is an inhibitor of P-gp.[1][28]
Advice To Patients
Inform patients that abiraterone acetate is available in different tablet formulations that are not interchangeable.[1][28]Importance of taking the corticosteroid as directed to minimize adverse effects of abiraterone.[1][28] If a dose of abiraterone or the corticosteroid is missed, take the next dose at the regularly scheduled time; importance of advising clinician if more than one daily dose of abiraterone is missed.[1][28]For patients currently receiving gonadotropin-releasing hormone (GnRH) agonist therapy, importance of continuing this therapy during abiraterone therapy.[1][28]Risk of increased abiraterone exposure and adverse effects if the conventional formulation is taken with food.[1] Advise patients to consume no food for at least 2 hours before or 1 hour after a dose of the conventional formulation.[1]Advise patients to swallow abiraterone acetate conventional or micronized tablets whole with water; do not crush or chew the tablets.[1][28]Risk of peripheral edema, hypertension, and hypokalemia (with potential to cause QT-interval prolongation or torsades de pointes).[1][28] Importance of patients informing their clinician if dizziness, palpitations, tachycardia, feelings of faintness or lightheadedness, headache, confusion, leg pain, muscle weakness, or peripheral edema occurs.[1][28]Risk of adrenocortical insufficiency.[1][28] Importance of patients informing their clinician if symptoms of adrenocortical insufficiency occur.[1][28]Risk of severe hepatotoxicity and importance of liver function test monitoring.[1][28] Importance of patients immediately informing their clinician if jaundice, dark urine, or severe nausea or vomiting occurs.[1][28]Increased risk of treatment-related mortality and fractures in patients receiving abiraterone acetate in combination with a corticosteroid and radium Ra 223 dichloride.[1][28] Use of abiraterone acetate in combination with a corticosteroid and radium Ra 223 dichloride is not recommended outside of a clinical trial.[1][28]Risk of severe hypoglycemia in patients with diabetes mellitus receiving concomitant abiraterone acetate and repaglinide or thiazolidinedione-containing medications.[1][28] Importance of monitoring blood glucose concentrations and adjusting antihyperglycemic agents as necessary.[1][28]Advise patients that abiraterone may cause fetal harm and potential loss of pregnancy; it is not known whether the drug distributes into semen.[1][28] Advise men to use an effective contraceptive method during sexual encounters with women of reproductive potential; these contraceptive measures are required during and for 3 weeks after discontinuance of abiraterone therapy.[1][28] Advise patients that women who are or may become pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).[1][28]Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.[1][28]Inform patients of other important precautionary information.[1][28]
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
| Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
| Oral | Tablets | 250 mg* | Zytiga® | Janssen Biotech |
| Abiraterone Acetate Tablets | ||||
| Tablets, film-coated | 500 mg* | Zytiga® | Janssen Biotech | |
| Abiraterone Acetate Film-coated Tablets | ||||
| Tablets (micronized) | 125 mg | Yonsa® | Sun Pharmaceutical Industries |
\* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
†Use is not currently included in the labeling approved by the US Food and Drug Administration.
1. Janssen Biotech Inc. Zytiga® (abiraterone acetate) tablets prescribing information. Horsham, PA; 2021 Aug. (https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e338e89-3cf2-48eb-b6e2-a06c608c6513)
2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202379orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf)
3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202379: Summary review for abiraterone. From FDA website. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000SumR.pdf)
4. de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364:1995-2005. (PubMed: 21612468)
5. Reid AH, Attard G, Danila DC et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010; 28:1489-95. (PubMed: 20159823)
6. Salem M, Garcia JA. Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. Curr Oncol Rep. 2011; 13:92-6. (PubMed: 21243537)
7. Attard G, Reid AH, A'Hern R et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009; 27:3742-8. (PubMed: 19470933)
8. Attard G, Reid AH, Yap TA et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008; 26:4563-71. (PubMed: 18645193)
9. Attard G, Richards J, de Bono JS. New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Clin Cancer Res. 2011; 17:1649-57. (PubMed: 21372223)
10. Massard C, Fizazi K. Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res. 2011; 17:3876-83. (PubMed: 21680543)
11. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004; 25:276-308. (PubMed: 15082523)
12. Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011; 185:787-94. (PubMed: 21239012)
13. Ryan CJ, Smith MR, Fong L et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010; 28:1481-8. (PubMed: 20159824)
14. Danila DC, Morris MJ, de Bono JS et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010; 28:1496-501. (PubMed: 20159814)
15. Janssen. Titusville, NJ: Personal communication.
16. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202379orig1s000: Medical review(s). From FDA website. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf)
17. Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000; 68:384-90. (PubMed: 11061578)
18. . Abiraterone acetate (Zytiga) for metastatic castration-resistant prostate cancer. Med Lett Drugs Ther. 2011; 53:63-4. (PubMed: 21836546)
19. Thomae BA, Eckloff BW, Freimuth RR et al. Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies. Pharmacogenomics J. 2002; 2:48-56. (PubMed: 11990382)
20. Ryan CJ, Smith MR, de Bono JS et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013; 368:138-48. (PubMed: 23228172) (DOI: 10.1056/NEJMoa1209096)
21. Rathkopf DE, Smith MR, de Bono JS et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014; 66:815-25. (PubMed: 24647231) (DOI: 10.1016/j.eururo.2014.02.056)
22. Ryan CJ, Smith MR, Fizazi K et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015; 16:152-60. (PubMed: 25601341) (DOI: 10.1016/S1470-2045(14)71205-7)
23. Fizazi K, Tran N, Fein L et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017; 377:352-360. (PubMed: 28578607) (DOI: 10.1056/NEJMoa1704174)
24. Fizazi K, Tran N, Fein L et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019; 20:686-700. (PubMed: 30987939) (DOI: 10.1016/S1470-2045(19)30082-8)
25. Fizazi K, Scher HI, Molina A et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012; 13:983-92. (PubMed: 22995653) (DOI: 10.1016/S1470-2045(12)70379-0)
26. Logothetis CJ, Basch E, Molina A et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012; 13:1210-7. (PubMed: 23142059) (DOI: 10.1016/S1470-2045(12)70473-4)
27. Mulders PF, Molina A, Marberger M et al. Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy. Eur Urol. 2014; 65:875-83. (PubMed: 24099659) (DOI: 10.1016/j.eururo.2013.09.005)
28. Sun Pharmaceutical Industries Inc. Yonsa® (abiraterone acetate) tablets prescribing information. Cranbury, NJ; 2022 July (https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b8967e10-f768-47ce-ac9e-2324c8390132)
29. Stein CA, Levin R, Given R et al. Randomized phase 2 therapeutic equivalence study of abiraterone acetate fine particle formulation vs. originator abiraterone acetate in patients with metastatic castration-resistant prostate cancer: The STAAR study. Urol Oncol. 2018; 36:81.e9-81.e16. (PubMed: 29150328) (DOI: 10.1016/j.urolonc.2017.10.018)
30. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210308orig1s000: Summary review(s). From FDA website. (https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210308Orig1s000TOC.cfm)
31. James ND, de Bono JS, Spears MR et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017; 377:338-351. (PubMed: 28578639) (DOI: 10.1056/NEJMoa1702900)
32. Morris MJ, Rumble RB, Basch E et al. Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018; 36:1521-1539. (PubMed: 29608397) (DOI: 10.1200/JCO.2018.78.0619)
33. Virgo KS, Rumble RB, de Wit R et al. Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. J Clin Oncol. 2021; 39:1274-1305. (PubMed: 33497248) (DOI: 10.1200/JCO.20.03256)
34. Hoyle AP, Ali A, James ND et al. Abiraterone in ''High-'' and ''Low-risk'' Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2019; 76:719-728. (PubMed: 31447077) (DOI: 10.1016/j.eururo.2019.08.006)
35. Goldwater R, Hussaini A, Bosch B et al. Comparison of a Novel Formulation of Abiraterone Acetate vs. the Originator Formulation in Healthy Male Subjects: Two Randomized, Open-Label, Crossover Studies. Clin Pharmacokinet. 2017; 56:803-813. (PubMed: 28425029) (DOI: 10.1007/s40262-017-0536-2)
10002. James ND, de Bono JS, Spears MR, et al for the STAMPEDE investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-51.
10003. Attard G, Murphy L, Clarke NW, et al on behalf of the STAMPEDE investigators. Abiraterone and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomized controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022;399:447-60.
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