Mechanism of Androgen Synthesis Inhibitors
Androgen synthesis inhibitors act by targeting the biosynthesis pathways of androgens: testosterone and dihydrotestosterone (DHT), known to facilitate prostate cancer progression. Abiraterone, a potent inhibitor, impedes enzymatic reactions responsible for androgen synthesis in adrenal glands and malignant tissues.
Its efficacy is primarily due to the inhibition of the CYP17 enzyme, leading to decreased concentrations of circulating and intratumoral testosterone and DHT.2 This specific mechanism hinders androgen-responsive pathways in metastatic cancer cells, mitigating their proliferation. Thus, abiraterone becomes a viable option for patients resistant to conventional ADT.
Clinical Trials Supporting Abiraterone Efficacy
A comprehensive study published in the New England Journal of Medicine denotes abiraterone’s ability to enhance radiographic progression-free survival in high-risk cohorts, presenting a 53% reduction in relative risk of progression or death.3 Furthermore, a 55.1% prostate-specific antigen response was observed in ADT-unresponsive patients following abiraterone administration.4
While these outcomes support the integration of abiraterone in therapeutic protocols, clinicians must be cognizant of potential side effects, including hypertension, fluid retention, hepatic enzyme abnormalities, among others.5
Survival Rates: A Comparative Analysis
Data from a clinical trial comprising 1,900 participants demonstrated a 93% survival rate at six years post-abiraterone intervention compared to 85% with ADT alone.6 Another study identified a 38% risk reduction in mortality three years post-treatment with abiraterone, with benefits evident at the 30-month checkpoint.3
Clinical responses to abiraterone may exhibit variations influenced by demographic and clinical variables such as age, disease phase, treatment antecedents, and comorbid conditions.7 Prior to therapeutic initiation, a thorough patient assessment is imperative.
Clinical Guidelines and Considerations
Abiraterone’s role in metastatic prostate cancer management is established, underlining the importance of accurate patient selection, treatment monitoring, and side effect vigilance.
Dosing protocols advocate for an initial 1000 mg daily administration for castration-resistant prostate cancer patients, augmented by prednisone doses adjusted to disease severity.8 For optimum pharmacokinetics, the 250 or 500 mg tablets are to be administered in a fasted state.8 Clinicians should remain alert to potential pharmacological interactions with agents, including but not limited to alpha-blockers and tyrosine kinase inhibitors.9
The integration of androgen synthesis inhibitors, especially abiraterone, into clinical practice promises to elevate treatment paradigms in advanced prostate cancer. It necessitates collaborative efforts between urology and family medicine disciplines to optimize therapeutic outcomes.
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Sources
1. Key Statistics for Prostate Cancer: Who Is at Risk? (2023, January 12). American Cancer Society. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html
2. Yin, L. & Hu, Q.Z. (2014). CYP17 inhibitors–abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nature Reviews Urology 11, 32-42.
3. Fizazi, K., Tran, N., Fein, L., Matsubara, N., Rodriguez-Antolin, A., Alekseev, B. Y., Özgüroğlu, M., Ye, D., Feyerabend, S., Protheroe, A., De Porre, P., Kheoh, T., Park, Y. C., Todd, M. B., Chi, K. N., LATITUDE Investigators (2017). Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. The New England Journal of Medicine 377(4), 352-360.
4. Kobayashi, K., Okuno, N., Arai, G., Nakatsu, H., Maniwa, A., Kamiya, N., Satoh, T., Kikukawa, H., Nasu, Y., Uemura, H., Nakashima, T., Mikami, K., Iinuma, M., Tanabe, K., Furukawa, J., & Kobayashi, H. (2021). Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study. Japanese Journal of Clinical Oncology 51(4), 544-551.
5. Abiraterone Side Effects. (2023, August 3). Drugs.com. https://www.drugs.com/sfx/abiraterone-side-effects.html
6. Attard, G., Murphy, L., Clarke, N. W., Cross, W., Jones, R. J., Parker, C. C., Gillessen, S., Cook, A., Brawley, C., Amos, C. L., Atako, N., Pugh, C., Buckner, M., Chowdhury, S., Malik, Z., Russell, J. M., Gilson, C., Rush, H., Bowen, J., Lydon, A., … Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators (2022). Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet (London, England) 399(10323), 447-460.
7. Prostate Cancer Treatment (PDQ®)–Patient Version. (2023, February 16). National Cancer Institute. https://www.cancer.gov/types/prostate/patient/prostate-treatment-pdq
8. Abiraterone (Oral Route). (2023, September 1). MayoClinic. https://www.mayoclinic.org/drugs-supplements/abiraterone-oral-route/proper-use/drg-20074889
9. Zytiga (abiraterone). (n.d.). MedBroadcast. Accessed September 14, 2023, from https://www.medbroadcast.com/drug/getdrug/zytiga