Abiraterone Acetate in Prostate Cancer: A Comprehensive Review of Mechanisms, Resistance, and Emerging Strategies

Abiraterone Acetate in Prostate Cancer: A Comprehensive Review of Mechanisms, Resistance, and Emerging Strategies

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Abiraterone acetate, a CYP17A1 inhibitor, has revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC). By disrupting androgen biosynthesis, it significantly extends survival and improves quality of life for many patients. However, its efficacy is limited by the development of resistance, highlighting the need for a deeper understanding of its mechanism of action, resistance mechanisms, and strategies to overcome these limitations. This review provides a comprehensive overview of abiraterone’s mechanism of action, including the complexities of CYP17A1 inhibition and extra-gonadal androgen production. It then critically examines established and emerging mechanisms of resistance, from androgen receptor (AR) alterations and bypass pathways to glucocorticoid receptor (GR) activation and intratumoral androgen synthesis. Finally, the review discusses current research aimed at predicting treatment response, preventing resistance, and optimizing abiraterone-based therapies, including combination strategies, novel androgen signaling inhibitors, and personalized approaches based on genomic and transcriptomic profiling.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Prostate cancer remains a leading cause of cancer-related mortality in men worldwide. Androgen deprivation therapy (ADT), traditionally achieved through surgical or chemical castration, has been the cornerstone of treatment for advanced prostate cancer. However, most patients eventually progress to castration-resistant prostate cancer (CRPC), where the disease continues to grow despite castrate levels of testosterone. The introduction of abiraterone acetate, a potent inhibitor of CYP17A1, marked a significant advancement in the treatment of mCRPC. Approved by the FDA in 2011 based on pivotal clinical trials (e.g., COU-AA-301 and COU-AA-302), abiraterone, in combination with prednisone, significantly improved overall survival and radiographic progression-free survival compared to placebo in patients with mCRPC, both before and after docetaxel chemotherapy [1, 2].

While abiraterone has undoubtedly improved patient outcomes, its efficacy is not universal, and resistance invariably develops. Understanding the intricate mechanisms underlying abiraterone’s activity, as well as the pathways by which prostate cancer cells circumvent its effects, is crucial for developing more effective and durable treatment strategies. This review aims to provide an in-depth analysis of abiraterone, covering its mechanism of action, resistance mechanisms, ongoing clinical trials, and future directions for optimizing its use in the management of prostate cancer.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Mechanism of Action: CYP17A1 Inhibition and Beyond

Abiraterone acetate is a prodrug that is rapidly converted in vivo to its active form, abiraterone. Abiraterone inhibits CYP17A1, a crucial enzyme in androgen biosynthesis. CYP17A1 catalyzes two sequential reactions: 17α-hydroxylation of pregnenolone and progesterone, leading to the formation of 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, respectively; and C17,20-lyase activity, converting 17α-hydroxypregnenolone and 17α-hydroxyprogesterone to dehydroepiandrosterone (DHEA) and androstenedione, respectively. These androgen precursors are then converted to testosterone and dihydrotestosterone (DHT), the primary androgen receptor (AR) ligand in prostate cancer cells [3].

By inhibiting CYP17A1, abiraterone effectively suppresses androgen production in the testes, adrenal glands, and prostate cancer cells themselves. This leads to a significant reduction in circulating and intratumoral androgens, thereby inhibiting AR signaling and tumor growth. The requirement for concurrent prednisone administration is crucial to mitigate the mineralocorticoid excess caused by CYP17A1 inhibition. Reduced cortisol production leads to an increase in ACTH, which in turn drives the production of mineralocorticoids like aldosterone, leading to hypertension, hypokalemia, and fluid retention. Prednisone suppresses ACTH production, thereby preventing these side effects [4].

It’s important to note that CYP17A1 inhibition is not absolute. While abiraterone significantly reduces androgen levels, it does not completely eliminate them. Residual androgen synthesis can contribute to the development of resistance, particularly through intratumoral androgen production. Furthermore, the downstream effects of CYP17A1 inhibition extend beyond androgen suppression. Alterations in the levels of other steroid hormones, such as pregnenolone and progesterone, may have unintended consequences on other signaling pathways, further complicating the therapeutic landscape.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Mechanisms of Resistance to Abiraterone

Despite its initial efficacy, resistance to abiraterone inevitably develops. The mechanisms of resistance are complex and multifactorial, involving both AR-dependent and AR-independent pathways. Understanding these mechanisms is crucial for developing strategies to overcome resistance and improve treatment outcomes.

3.1 Androgen Receptor (AR) Amplification and Mutation

One of the most well-established mechanisms of resistance is AR amplification and mutation. Increased AR gene copy number leads to elevated AR protein levels, making the cells more sensitive to even low levels of androgens. Mutations in the AR ligand-binding domain (LBD) can alter the receptor’s specificity, allowing it to be activated by non-canonical ligands, such as adrenal androgens or even synthetic progestins. Several AR mutations have been identified in abiraterone-resistant tumors, including T878A and W742C, which can broaden the AR’s ligand specificity and increase its activity [5, 6].

3.2 AR Splice Variants

AR splice variants, particularly AR-V7, are another important mechanism of resistance. AR-V7 lacks the ligand-binding domain but retains the DNA-binding domain and transactivation domain, allowing it to constitutively activate AR target genes in the absence of ligand. The presence of AR-V7 in circulating tumor cells (CTCs) has been shown to be a predictor of resistance to both abiraterone and enzalutamide [7]. Other AR splice variants, such as ARv567es, can also contribute to resistance by activating AR signaling independently of androgens [8].

3.3 Intratumoral Androgen Synthesis

As mentioned earlier, abiraterone does not completely eliminate androgen production. Prostate cancer cells can adapt and upregulate alternative pathways for androgen synthesis, particularly within the tumor microenvironment. This intratumoral androgen synthesis can bypass the effects of abiraterone and maintain AR signaling [9]. Enzymes such as AKR1C3 can convert adrenal androgens like androstenedione to testosterone, contributing to intratumoral androgen levels [10].

3.4 Activation of Bypass Signaling Pathways

Besides AR-dependent mechanisms, AR-independent pathways can also contribute to abiraterone resistance. Activation of other signaling pathways, such as the PI3K/AKT/mTOR pathway, can promote cell survival and proliferation even in the absence of strong AR signaling. Cross-talk between AR signaling and these other pathways can also contribute to resistance [11]. Furthermore, the glucocorticoid receptor (GR) can be activated by elevated levels of glucocorticoids resulting from abiraterone treatment, leading to the expression of genes that promote cell survival and proliferation [12]. GR activation can also induce resistance to androgen receptor targeting agents.

3.5 Epithelial-Mesenchymal Transition (EMT)

EMT is a process by which epithelial cells lose their cell-cell adhesion and acquire a mesenchymal phenotype, characterized by increased motility and invasiveness. EMT has been implicated in resistance to various cancer therapies, including abiraterone. EMT can promote tumor cell survival and metastasis, and it can also alter the expression of AR and other signaling proteins, leading to resistance [13].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Predictive Biomarkers and Personalized Therapy

Identifying biomarkers that can predict response to abiraterone is crucial for personalizing treatment and avoiding unnecessary exposure to ineffective therapies. Several potential biomarkers have been identified, including:

• AR-V7: As mentioned earlier, the presence of AR-V7 in CTCs is associated with resistance to abiraterone.
• Androgen Receptor Expression: While high AR expression is generally associated with increased sensitivity to androgen deprivation, the relationship between AR expression and abiraterone response is complex. Some studies have shown that high AR expression is associated with better response, while others have found no correlation or even an association with resistance. The context of AR expression, including the presence of AR mutations or splice variants, likely influences its predictive value.
• Genomic Profiling: Next-generation sequencing (NGS) can identify genomic alterations, such as AR amplification, mutations, or deletions of tumor suppressor genes, that may predict response to abiraterone. For example, mutations in DNA repair genes, such as BRCA2, have been associated with increased sensitivity to platinum-based chemotherapy and PARP inhibitors, which may be considered as alternative treatments in patients with these mutations.
• Transcriptomic Profiling: RNA sequencing can identify gene expression signatures that are associated with response or resistance to abiraterone. These signatures may reflect the activation of bypass signaling pathways or the upregulation of androgen synthesis enzymes.
• Circulating Tumor Cells (CTCs) and circulating tumor DNA (ctDNA): Serial monitoring of CTCs and ctDNA can provide real-time information about treatment response and the development of resistance mechanisms. Changes in AR-V7 levels, the emergence of AR mutations, or the presence of other resistance-related biomarkers in CTCs or ctDNA can alert clinicians to the need for treatment modification.

5. Combination Strategies and Novel Therapies

Given the complexity of abiraterone resistance, combination strategies are being explored to improve treatment outcomes. These strategies aim to target multiple pathways involved in resistance or to enhance the efficacy of abiraterone.

• Abiraterone with Chemotherapy: Combining abiraterone with chemotherapy, such as docetaxel or cabazitaxel, has shown promise in clinical trials. The synergistic effect of these agents may overcome resistance mechanisms and improve survival [14].
• Abiraterone with PARP Inhibitors: In patients with mutations in DNA repair genes, combining abiraterone with PARP inhibitors, such as olaparib or rucaparib, may enhance DNA damage and promote tumor cell death [15].
• Abiraterone with PI3K/AKT/mTOR Inhibitors: Targeting the PI3K/AKT/mTOR pathway, which is often activated in abiraterone-resistant tumors, may enhance the efficacy of abiraterone. Several clinical trials are evaluating the combination of abiraterone with PI3K, AKT, or mTOR inhibitors [16].
• Next-Generation Androgen Receptor Inhibitors: Drugs such as enzalutamide and darolutamide show improved survival and side effect profiles. Combinations of these therapies with abiraterone are being explored. [17, 18].
• Combination with Radiotherapy: Combining abiraterone with stereotactic body radiotherapy (SBRT) to oligometastatic disease has shown promising results in select patient populations. This approach aims to eradicate localized disease and potentially delay the emergence of widespread resistance [19].

In addition to combination strategies, novel therapies are being developed to target AR signaling and other pathways involved in abiraterone resistance. These include:

• Selective Androgen Receptor Degraders (SARDs): SARDs are a new class of drugs that induce the degradation of the AR protein, rather than simply blocking its activity. This approach may be more effective in overcoming resistance mechanisms related to AR overexpression or mutation [20].
• CYP11A1 Inhibitors: These agents act on the upstream target of CYP17A1 and block synthesis of all steroid hormones. Osilodrostat is an example of a CYP11A1 inhibitor. [21]
• Immunotherapy: Immunotherapy, such as checkpoint inhibitors, has shown limited efficacy in prostate cancer as a monotherapy. However, combination strategies with other agents, such as abiraterone, are being explored to enhance the immune response against prostate cancer cells [22].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Clinical Trials and Ongoing Research

Numerous clinical trials are currently investigating abiraterone in various settings, including:

• First-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC): Studies are evaluating the addition of abiraterone to ADT in patients with mHSPC to improve long-term outcomes.
• Combination with novel agents: Trials are testing the combination of abiraterone with other targeted therapies, such as PARP inhibitors, PI3K inhibitors, and SARDs, to overcome resistance mechanisms.
• Biomarker-driven trials: Studies are using genomic and transcriptomic profiling to identify patients who are most likely to benefit from abiraterone-based therapies.

Ongoing research is focused on: improving drug delivery methods, developing new AR inhibitors, and targeting the tumor microenvironment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Conclusion

Abiraterone acetate has significantly improved the treatment of mCRPC, but its efficacy is limited by the development of resistance. Understanding the complex mechanisms underlying abiraterone’s activity and resistance is crucial for developing more effective and durable treatment strategies. Emerging research is focused on identifying predictive biomarkers, developing combination strategies, and discovering novel therapies that can overcome resistance and improve outcomes for patients with prostate cancer. The future of abiraterone-based therapy lies in personalized approaches that consider the individual patient’s genomic profile, disease characteristics, and treatment history.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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