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Abiraterone: Mechanism, Adverse Effects, Contraindications, and Dosage

Indications for Abiraterone

Castration-Sensitive Metastatic Prostate Carcinoma (M1 CSPC)

Abiraterone is an treatment option for men with high-risk castration-sensitive metastatic prostate cancer. Gleason score ≥8, at least three bone metastases, or the presence of visceral metastases were defined as high-risk tumor. The approval of abiraterone was based on the results of the STAMPEDE trial (James et al., 2017) and LATITUDE trial (Fizazi et al., 2017). The combination of standard Androgen deprivation therapy with abiraterone 1000 mg/d and prednisolone 5 mg/d resulted in improved survival (83% vs. 76%), prolonged progression-free survival and prolonged time to chemotherapy.

Castration-Resistant Metastatic Prostate Cancer (M1 CRPC)

Abiraterone is an option to treat men with castration-resistant metastatic prostate cancer before or after chemotherapy. Abiraterone increases survival in patients with CRPC after docetaxel chemotherapy (14.8 vs. 10.9 months) compared to placebo (Bono et al., 2011). Abiraterone also improves prognosis before docetaxel chemotherapy treatment in patients with M1 CRPC: prolonged progression-free survival (16.5 vs. 8.3 months) and overall survival (Ryan et al., 2013).

Abiraterone is not approved for the treatment of increasing PSA levels under classical androgen deprivation therapy and without the detection of metastases in imaging (M0 CRPC).

PARP inhibitor olaparib with abiraterone:

The combination of olaparib with abiraterone showed in the PROpel trial in patients with M1 CRPC and ineligible for chemotherapy (regardless of BRCA mutation status) prolonged progression-free survival (25 vs. 17 months) and overall survival (42 vs. 35 months) (Saad et al., 2023). However, the subgroup analysis showed only a slight advantage in overall survival in patients without BRCA mutations (HR 0.91, 40 vs. 38 months), while the difference in overall survival was overly clear in patients with BRCA mutations (HR 0.29). The combination of abiraterone, prednisolone, and olaparib has been approved as a first-line treatment for M1 CRPC in Europe without genetic testing since 2023. In the USA, approval was restricted to patients with BRCA mutations; there are concerns regarding the risk-benefit ratio in patients without BRCA mutations.

Mechanism of Action of Abiraterone

Abiraterone is a CYP-17 inhibitor and thus an inhibitor of the testosterone biosynthesis.

Pharmacokinetics of Abiraterone

Taking Abiraterone with meals leads to a massive increase in absorption with up to 17-fold increase in peak concentration, therefore intake with meals must be avoided (see dosage). High distribution volume and high plasma protein binding. Elimination half life 15 h, hepatic metabolism and biliary elimination.

Adverse Effects of Abiraterone

• Hepatotoxicity with increased GOT and GPT
• Fluid retention with peripheral edema as a result of mineralcorticoid excess with hypertension and hypokalemia
• Abiraterone leads to a decrease in bone density
• Urinary tract infection

Interactions with Abiraterone

Abiraterone inhibits the enzyme CYP2D6, therefore dose reduction or caution with metoprolol, propranolol, desimpramine, haloperidol, risperidone, propafenone, flecanide, codeine, oxycodone and tramadol.

Contraindications for Abiraterone

• Allergy and intolerance
• Women and children
• Moderate or severe hepatic impairment (Child-Pugh B and C)
• Hepatotoxicity during treatment (ALT and/or AST greater than 5× upper limit of normal value or total bilirubin greater than 3× ULN

Dosage of Abiraterone

The dosage of abiraterone is 1000 mg 1-0-0 p.o. Abiraterone must be taken on an empty stomach, no food should be consumed for at least two hours before the dose and for at least one hour after the dose. Abiraterone is prescribed together with Prednisolone 10 mg 1-0-0.

Brand Name of Abiraterone:

Zytiga.

References

de Bono, J. S.; Logothetis, C. J.; Molina, A.; Fizazi, K.; North, S.; Chu, L.; Chi, K. N.; Jones, R. J.; Goodman, O. B.; Saad, F.; Staffurth, J. N.; Mainwaring, P.; Harland, S.; Flaig, T. W.; Hutson, T. E.; Cheng, T.; Patterson, H.; Hainsworth, J. D.; Ryan, C. J.; Sternberg, C. N.; Ellard, S. L.; Fléchon, A.; Saleh, M.; Scholz, M.; Efstathiou, E.; Zivi, A.; Bianchini, D.; Loriot, Y.; Chieffo, N.; Kheoh, T.; Haqq, C. M.; Scher, H. I. & Investigators, C. O. U. A. Abiraterone and increased survival in metastatic prostate cancer.
N Engl J Med, 2011, 364, 1995-2005

Ryan, C. J.; Smith, M. R.; de Bono, J. S.; Molina, A.; Logothetis, C. J.; de Souza, P.; Fizazi, K.; Mainwaring, P.; Piulats, J. M.; Ng, S.; Carles, J.; Mulders, P. F. A.; Basch, E.; Small, E. J.; Saad, F.; Schrijvers, D.; Poppel, H. V.; Mukherjee, S. D.; Suttmann, H.; Gerritsen, W. R.; Flaig, T. W.; George, D. J.; Yu, E. Y.; Efstathiou, E.; Pantuck, A.; Winquist, E.; Higano, C. S.; Taplin, M.; Park, Y.; Kheoh, T.; Griffin, T.; Scher, H. I.; Rathkopf, D. E. & Investigators, C. O. U. A. Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med, 2013, 368, 138-148.

F. Saad et al., “PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).,” Journal of Clinical Oncology, vol. 40, no. 6suppl, p. 11, 2022.

  Deutsche Version: Abirateron

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