Zytiga (Abiraterone Acetate)
Abiraterone — Approved Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Metastatic castration-resistant prostate cancer (mCRPC) | Adult males | Combination with prednisone 5 mg BID + GnRH analog/orchiectomy | FDA Approved |
| Metastatic high-risk castration-sensitive prostate cancer (mCSPC) | Adult males | Combination with prednisone 5 mg QD + GnRH analog/orchiectomy | FDA Approved |
Abiraterone acetate is an oral, first-in-class CYP17 inhibitor that blocks androgen biosynthesis in the testes, adrenal glands, and prostate tumour tissue. It was first approved in 2011 for post-docetaxel mCRPC (COU-AA-301) and subsequently gained approval for chemo-naïve mCRPC (COU-AA-302) and metastatic high-risk CSPC (LATITUDE). The STAMPEDE trial provided additional evidence in newly diagnosed metastatic and locally advanced prostate cancer. Abiraterone must always be co-prescribed with prednisone (or prednisolone) to mitigate mineralocorticoid excess caused by CYP17 inhibition, and patients must maintain concurrent androgen deprivation with a GnRH analog or prior bilateral orchiectomy (FDA PI).
Non-metastatic CRPC (high-risk biochemical recurrence): Explored in SPARTAN-related studies; enzalutamide and related agents are preferred in this setting. Evidence quality: Low.
Abiraterone Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| mCRPC — post-docetaxel or chemo-naïve | 1000 mg PO QD | 1000 mg PO QD | 1000 mg/day | + Prednisone 5 mg PO BID Must take on empty stomach; continue until progression |
| mCSPC — high-risk, newly diagnosed | 1000 mg PO QD | 1000 mg PO QD | 1000 mg/day | + Prednisone 5 mg PO QD (not BID) Lower prednisone dose than mCRPC; LATITUDE-based |
| Moderate hepatic impairment (Child-Pugh B) | 250 mg PO QD | 250 mg PO QD | 250 mg/day | Monitor LFTs weekly × 1 month, then q2 weeks × 2 months, then monthly |
| With strong CYP3A4 inducer (unavoidable) | 1000 mg PO BID | 1000 mg PO BID | 2000 mg/day | Only during co-administration period; return to QD when inducer stopped |
| Hepatotoxicity dose reduction (1st event) | 750 mg PO QD | 750 mg PO QD | 750 mg/day | Resume after LFTs return to baseline or ALT/AST ≤2.5× ULN + bilirubin ≤1.5× ULN |
| Hepatotoxicity dose reduction (2nd event) | 500 mg PO QD | 500 mg PO QD | 500 mg/day | Discontinue if hepatotoxicity recurs at 500 mg |
Abiraterone must be taken on an empty stomach. Do not eat food for 2 hours before and 1 hour after taking the dose. Food increases abiraterone Cmax up to 17-fold and AUC up to 10-fold (high-fat meal). The safety of these dramatically increased exposures has not been assessed with repeated dosing, and highly variable absorption with food could lead to unpredictable toxicity. Tablets must be swallowed whole — do not crush or chew. All patients must also receive concurrent ADT (GnRH analog or bilateral orchiectomy) and prednisone (FDA PI).
Abiraterone Pharmacology
Mechanism of Action
Abiraterone acetate is a prodrug that is rapidly converted by esterases to abiraterone, a selective, irreversible inhibitor of CYP17A1 (17α-hydroxylase/C17,20-lyase). CYP17A1 is a key enzyme in the androgen biosynthesis pathway, catalysing two sequential reactions: the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives, and the subsequent formation of DHEA and androstenedione. By inhibiting CYP17A1, abiraterone blocks androgen production at all three sources: the testes, the adrenal glands, and the tumour itself. This is critical because standard androgen deprivation therapy (GnRH analogs or orchiectomy) only suppresses testicular androgen production. Upstream CYP17 blockade also diverts steroidogenesis toward mineralocorticoid precursors, causing hypertension, hypokalemia, and fluid retention — hence the requirement for concurrent prednisone to suppress ACTH-driven mineralocorticoid excess.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~2 h; food increases Cmax 7–17× and AUC 5–10×; 2-fold accumulation at steady state | Must take fasting (no food 2 h before and 1 h after). Food effect is the most extreme of any oral oncology drug — counsel all patients. |
| Distribution | Vss ~19,669 L (apparent); protein binding >99% (albumin, α1-AGP) | Very large apparent volume reflects extensive tissue distribution. Dialysis not effective. |
| Metabolism | Prodrug → abiraterone (esterases, not CYP); abiraterone → abiraterone sulphate (SULT2A1, inactive, ~43% of exposure) + N-oxide abiraterone sulphate (CYP3A4 + SULT2A1, inactive, ~43%) | CYP3A4 involved in metabolite formation; strong CYP3A4 inducers reduce exposure 55%. Abiraterone itself inhibits CYP2D6 and CYP2C8. |
| Elimination | t½ ~12 h; feces 88% (55% unchanged prodrug + 22% abiraterone), urine 5% | No renal dose adjustment needed (including ESRD on dialysis). Hepatic impairment significantly increases exposure (3.6-fold moderate, 7-fold severe). |
Abiraterone Side Effects
Safety data are based on pooled analysis from 5 randomised placebo-controlled trials (n=2,230 abiraterone-treated patients). Adverse reaction rates differ between the mCRPC trials (prednisone 5 mg BID) and the LATITUDE mCSPC trial (prednisone 5 mg QD), particularly for mineralocorticoid-related events.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fatigue | 39% (COU-AA-302) | Includes asthenia; Grade 3-4 in ~2% |
| Arthralgia / joint swelling | 30% | Includes joint stiffness; Grade 3-4 in 2–4% |
| Hypertension | 8.5–37% | LATITUDE 37% (Grade 3-4 20%!); mCRPC trials 8.5–22%. Mineralocorticoid excess; correct before starting |
| Edema | 25–27% | Peripheral; Grade 3-4 in <2% |
| Hypokalemia | 17–30% | LATITUDE 30% (Grade 3-4 10%); mCRPC 17–28% (Grade 3-4 4–5%). Mineralocorticoid effect; monitor monthly |
| Hot flush | 15–22% | ADT class effect; rarely severe |
| Diarrhea | 18–22% | Usually mild; Grade 3-4 <1% |
| Muscle discomfort | 26% | Includes muscle spasms, myalgia; Grade 3-4 in 3% |
| Nausea | 14–22% | Across trials; rarely Grade 3+ |
| Cough | 11–17% | Non-productive |
| Upper respiratory tract infection | 5–13% | Higher in COU-AA-302 (13%); rarely severe |
| Constipation | 23% | COU-AA-302; manage with standard measures |
| Contusion / bruising | 13% | COU-AA-302 |
| Insomnia | 14% | COU-AA-302 |
| Dyspnea | 12% | COU-AA-302; Grade 3-4 in 2.4% |
| ALT / AST increase | 11–46% | LATITUDE ALT 46%; typically in first 3 months. Grade 3-4 ALT in 1.4–6.4%. Monitor LFTs closely |
| Urinary tract infection | 7–12% | COU-AA-301: 12% |
| Headache | ≥10% (pooled) | LATITUDE 7.5%; appears in pooled highlights as ≥10% with >2% difference from placebo |
| Vomiting | ≥10% (pooled) | Listed in pooled highlights as ≥10% with >2% difference from placebo |
| Hematuria | 10% | COU-AA-302; Grade 3-4 in 1.3% |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Arrhythmia | 7.2% | Includes AF, tachycardia, bradycardia; mostly Grade 1-2; QT prolongation and Torsades de Pointes reported postmarketing (with hypokalemia) |
| Fractures (non-pathological) | 5.9% | COU-AA-301; Grade 3-4 in 1.4% |
| Cardiac failure | 2.6% | Pooled: Grade 3-4 1.3%; led to 5 discontinuations and 4 deaths (vs 0.2% Grade 3-4 placebo) |
| Rash | 8.1% | COU-AA-302 |
| Dyspepsia | 6–11% | COU-AA-301 6.1%, COU-AA-302 11% |
| Urinary frequency / nocturia | 6–7% | COU-AA-301 |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (ALT/AST ≥5× ULN) | 6% of 2230 patients | Typically first 3 months | Hold abiraterone; resume at 750 mg then 500 mg per stepdown. Discontinue if ALT >3× ULN + bilirubin >2× ULN. Fulminant hepatitis and deaths reported postmarketing |
| Cardiac failure | 2.6% (Grade 3-4: 1.3%) | Variable | Exclude patients with LVEF <50% or NYHA III-IV; monitor for signs of heart failure; treatment discontinuation in 0.2% |
| Severe hypokalemia (Grade 3-4) | 4% (mCRPC); 10% (mCSPC) | Early; ongoing | Correct before starting treatment; monitor monthly; QT prolongation and Torsades de Pointes may occur; potassium supplementation as needed |
| Adrenocortical insufficiency | 0.3% | Risk with prednisone interruption/stress | Increase corticosteroid dose before, during, and after stressful situations. Do not abruptly stop prednisone |
| Severe hypoglycemia | Rare (with TZDs/repaglinide) | Variable | Monitor blood glucose in diabetic patients on thiazolidinediones or repaglinide; adjust antidiabetic doses |
The LATITUDE trial (mCSPC) used prednisone 5 mg once daily instead of the 5 mg twice daily used in the mCRPC trials. This lower prednisone dose provides less mineralocorticoid suppression, resulting in significantly higher rates of Grade 3-4 hypokalemia (10% vs 4%) and Grade 3-4 hypertension (20% vs 2%). Clinicians using abiraterone in the CSPC setting should anticipate more intensive blood pressure and potassium monitoring, especially in patients with pre-existing cardiovascular conditions (FDA PI).
Abiraterone Drug Interactions
Abiraterone is metabolised primarily by CYP3A4/SULT2A1 and is itself an inhibitor of CYP2D6 and CYP2C8. Notably, strong CYP3A4 inhibitors do not meaningfully increase abiraterone exposure (ketoconazole had no clinically meaningful effect), but strong CYP3A4 inducers reduce it by 55%. Abiraterone’s CYP2C8 inhibition has a clinically important consequence: severe hypoglycemia when co-prescribed with CYP2C8-dependent antidiabetic agents.
Abiraterone Monitoring Parameters
- Blood pressureAt least monthly
RoutineHypertension from mineralocorticoid excess: Grade 3-4 in 2% (mCRPC) to 20% (LATITUDE mCSPC). Control BP before starting and at every visit. Closely monitor patients with underlying cardiovascular disease. - Serum potassiumAt least monthly
RoutineHypokalemia from mineralocorticoid excess: Grade 3-4 in 4–10%. Correct before starting treatment. Risk of QT prolongation and Torsades de Pointes if hypokalemia develops. - Hepatic function (ALT, AST, bilirubin)Every 2 weeks × 3 months, then monthly
RoutineGrade 3-4 transaminase elevations in 6%; typically first 3 months. Hold for ALT/AST >5× ULN or bilirubin >3× ULN. Permanently discontinue for concurrent ALT >3× ULN + bilirubin >2× ULN (Hy’s Law). Fulminant hepatitis and deaths reported. - Fluid retentionAt least monthly
RoutineEdema in 25–27%; Grade 3-4 in <2%. Weigh patients regularly; assess for signs of heart failure. - Blood glucoseAs indicated in diabetic patients
Trigger-basedSevere hypoglycemia reported with thiazolidinediones and repaglinide (CYP2C8 inhibition). Monitor closely and adjust antidiabetic medications. - Signs of adrenal insufficiencyOngoing; heightened during stress
Trigger-basedRisk 0.3%; symptoms may be masked by mineralocorticoid excess. Increase corticosteroid dose during surgery, illness, or stress. Do not abruptly stop prednisone.
Abiraterone Contraindications & Cautions
Absolute Contraindications
- None listed formally in the FDA PI (Section 4). However, do NOT use in patients with baseline severe hepatic impairment (Child-Pugh C) — abiraterone exposure increases ~7-fold and the fraction of unbound drug doubles (FDA PI §8.6).
Relative Contraindications (Specialist Input Recommended)
- Females who are or may become pregnant: CYP17 inhibition can cause fetal harm. Abiraterone caused developmental toxicity in rats at ≥0.03× human exposure. Tablets should not be handled by pregnant women.
- Concurrent radium Ra-223: ERA-223 trial showed increased fractures (28.6% vs 11.4%) and deaths. Not recommended outside clinical trials.
- LVEF <50% or NYHA Class III-IV heart failure: These patients were excluded from pivotal trials; cardiac failure occurred in 2.6% (Grade 3-4 1.3%).
Use with Caution
- Pre-existing cardiovascular disease, hypertension, or hypokalemia: Mineralocorticoid excess can worsen all three. Correct hypokalemia and control BP before starting.
- Moderate hepatic impairment (Child-Pugh B): Reduce dose to 250 mg QD with intensified LFT monitoring.
- Diabetes treated with thiazolidinediones or repaglinide: Severe hypoglycemia risk from CYP2C8 inhibition.
- Patients at risk of fractures: Non-pathological fractures in 5.9%; consider bone-protective agents.
In the ERA-223 trial, concurrent use of abiraterone plus prednisone with radium Ra-223 dichloride resulted in increased fractures (28.6% vs 11.4%) and increased mortality (38.5% vs 35.5%) compared to abiraterone plus prednisone with placebo. This combination is not recommended outside of controlled clinical trials (FDA PI §5.4).
Abiraterone Patient Counselling
Purpose of Therapy
Abiraterone blocks a protein called CYP17 that the body needs to make testosterone. Prostate cancer cells use testosterone to grow. By stopping testosterone production from all sources, abiraterone helps slow or stop cancer growth. It is always taken together with a low dose of prednisone (a steroid) and ongoing hormone therapy (an injection or prior surgery).
How to Take
Take abiraterone on an empty stomach — do not eat for 2 hours before and 1 hour after taking the tablets. Swallow tablets whole with water. Take prednisone exactly as prescribed — do not skip or stop prednisone without talking to your doctor, as this can cause serious problems with your adrenal glands.
Sources
- Zytiga (abiraterone acetate) Prescribing Information. Janssen Biotech Inc. Revised November 2024. Janssen LabelPrimary source for all dosing, indications, warnings, adverse reactions, pharmacokinetics, and drug interaction data.
- de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. doi:10.1056/NEJMoa1014618Phase III COU-AA-301 trial establishing abiraterone efficacy in post-docetaxel mCRPC; first approval-enabling trial.
- Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. doi:10.1056/NEJMoa1209096Phase III COU-AA-302 trial extending abiraterone indication to chemo-naïve mCRPC.
- Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174Phase III LATITUDE trial establishing abiraterone in high-risk mCSPC with OS benefit.
- 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(4):338-351. doi:10.1056/NEJMoa1702900STAMPEDE trial: abiraterone in newly diagnosed locally advanced or metastatic prostate cancer; OS benefit in metastatic subgroup.
- 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. Lancet Oncol. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8Final LATITUDE OS analysis confirming durable survival benefit of abiraterone in mCSPC.
- NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2026. NCCN.orgCurrent US consensus guideline positioning abiraterone in mCRPC and mCSPC treatment algorithms.
- Parker C, Castro E, Fizazi K, et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-1134. doi:10.1016/j.annonc.2020.06.011European guideline incorporating abiraterone across prostate cancer treatment settings.
- 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(23):3742-3748. doi:10.1200/JCO.2008.20.0642Phase I/II study establishing proof-of-concept for CYP17 inhibition in CRPC.
- Chi KN, Spratlin J, Kollmannsberger C, et al. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. J Clin Pharmacol. 2015;55(12):1406-1414. doi:10.1002/jcph.564Characterisation of the extreme food effect on abiraterone pharmacokinetics supporting fasting administration.
- Goldwater R, Kankam M, Geffner M, et al. A phase 1 study of the effect of hepatic impairment on abiraterone pharmacokinetics. Cancer Chemother Pharmacol. 2019;83(3):581-590. doi:10.1007/s00280-018-03764-yHepatic impairment PK study: 3.6-fold and 7-fold AUC increase in moderate and severe impairment respectively.
- Smith MR, Saad F, Rathkopf DE, et al. Clinical outcomes from androgen signaling-directed therapy after treatment with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302. Eur Urol. 2017;72(1):10-13. doi:10.1016/j.eururo.2017.03.007Post hoc COU-AA-302 analysis informing treatment sequencing after abiraterone in mCRPC.