Prostate cancer that continues to grow despite hormone-lowering treatment is classified as metastatic castration-resistant prostate cancer (mCRPC). This advanced stage led to the development of next-generation hormonal therapies, which target the androgen signaling pathway. Among the most effective options for treating mCRPC are two oral medications, Enzalutamide and Abiraterone, which are frequently compared due to their similar clinical roles. Understanding their differences in mechanism, efficacy, side effects, and administration is necessary to select the most appropriate treatment strategy.
How Each Drug Works
The fundamental difference between these two therapies lies in their pharmacological targets along the androgen synthesis and signaling pathway. Abiraterone is classified as an androgen biosynthesis inhibitor because it blocks the production of male hormones. It specifically inhibits the enzyme CYP17A1, which is involved in creating androgens in the testes, adrenal glands, and tumor tissue itself. By preventing androgen formation at the source, Abiraterone starves prostate cancer cells of the hormones needed for growth.
Enzalutamide operates further down the signaling cascade as an androgen receptor (AR) signaling inhibitor. This drug directly binds to the androgen receptor, the protein that androgens attach to in the cell nucleus to stimulate growth. Enzalutamide blocks the growth signal even if trace amounts of androgen are present. It achieves this by inhibiting androgen binding, preventing the receptor’s move to the nucleus, and blocking its interaction with DNA.
Treatment Sequencing and Indications
Both Enzalutamide and Abiraterone are approved for use across multiple stages of advanced prostate cancer, including metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). In the mCRPC setting, both agents are routinely used both before and after chemotherapy, such as docetaxel. Current guidelines generally allow either drug as a first-line therapy for mCRPC, with the choice depending on patient factors and anticipated side effects.
A significant challenge is cross-resistance, where using one drug diminishes the effectiveness of the other if used immediately afterward. Since both drugs target the same signaling pathway, the tumor develops resistance mechanisms that apply to both agents. Retrospective data suggests that using Abiraterone first, followed by Enzalutamide, may result in longer combined progression-free survival compared to the reverse sequence. Careful planning regarding treatment sequence is necessary to maximize a patient’s time on effective therapy.
Comparative Efficacy Results
Both drugs have demonstrated substantial benefits in overall survival (OS) and radiographic progression-free survival (rPFS) compared to placebo in clinical trials. However, a direct head-to-head comparison from a randomized study is not available. Indirect comparisons and meta-analyses provide some insights, suggesting that Enzalutamide may offer a small, statistically significant advantage in overall survival and time to next treatment compared to Abiraterone.
Enzalutamide has been linked to a higher rate of prostate-specific antigen (PSA) response and longer time to PSA progression in several comparative analyses. Some studies suggest Enzalutamide may be associated with a slightly longer average OS. Other studies focusing on metastatic hormone-sensitive prostate cancer have found no significant differences in time to progression or overall survival between the two agents. Overall efficacy is considered similar between the two therapies, but patient-specific factors often dictate the choice.
Distinct Side Effect Profiles
The unique mechanisms of action lead to distinct side effect profiles that influence treatment selection. Abiraterone’s inhibition of CYP17A1 can cause a buildup of mineralocorticoids, hormones that regulate salt and water balance. This often results in mineralocorticoid excess, manifesting as hypertension, hypokalemia, and fluid retention. To manage these effects, Abiraterone must be co-administered with a low dose of prednisone or prednisolone, a corticosteroid.
Enzalutamide does not require concurrent steroid treatment, but its side effects center on the central nervous system (CNS). The most common CNS effects include fatigue and weakness. There is also a risk of seizures. Furthermore, Enzalutamide is associated with higher rates of falls and fractures compared to Abiraterone, which is a concern for older patients.
Administration Requirements
A practical difference between the two drugs is the manner in which they must be taken orally. Abiraterone absorption is highly dependent on food intake, meaning it must be taken on an empty stomach to ensure consistent absorption. Patients are typically instructed to take the drug at least one hour before or two hours after a meal. This strict timing requirement can make adherence challenging.
Enzalutamide, by contrast, can be taken with or without food, offering greater flexibility in daily dosing. Abiraterone also requires the mandatory co-administration of a steroid to manage hormonal side effects. Patients taking Abiraterone require more frequent monitoring of blood pressure, potassium levels, and liver function tests due to the risk of mineralocorticoid and liver toxicity.