Prostate cancer is a common malignancy affecting men globally. Androgen Receptor Signaling Inhibitors (ARSIs) are an advanced class of medications used to treat this disease. This article explains what ARSIs are and their role in managing prostate cancer by targeting cancer growth drivers.
Prostate Cancer and the Role of Hormones
Prostate cancer often relies on male hormones, known as androgens, for its growth and proliferation. Testosterone and dihydrotestosterone (DHT) are the primary androgens in men, with testosterone mainly circulating in the bloodstream and DHT being the more active form within prostate tissues. These hormones bind to and activate the androgen receptor (AR) within prostate cells, including cancerous ones, stimulating their growth. Approximately 80-90% of prostate cancers are dependent on androgens at initial diagnosis.
Androgen deprivation therapy (ADT), also referred to as hormone therapy, works by reducing or blocking these male hormones. This can involve surgical removal of the testes (orchiectomy) or medical castration using drugs like GnRH agonists or antagonists, which lower testosterone production from the testes. By significantly reducing androgen levels, ADT aims to slow cancer growth and can cause prostate cancer cells to shrink or grow more slowly for a period. However, while ADT is initially effective, prostate cancer can eventually become resistant to these treatments, leading to what is known as castration-resistant prostate cancer (CRPC). This progression occurs despite low levels of testosterone, indicating that the cancer has found ways to continue growing.
How Androgen Receptor Signaling Inhibitors Work
Androgen Receptor Signaling Inhibitors (ARSIs) target the androgen pathway more comprehensively than traditional ADT by interfering with the androgen receptor (AR) signaling axis. These inhibitors work through distinct mechanisms to suppress androgen activity, even when the body’s overall testosterone levels are low. Some ARSIs block the production of androgens in the body, while others directly prevent androgens from binding to the receptor on cancer cells.
One mechanism involves inhibiting the enzyme CYP17 (cytochrome P450 17A1). This enzyme is found in the testes, adrenal glands, and prostate tumor tissues, playing a role in androgen biosynthesis. By blocking CYP17, drugs like abiraterone acetate reduce androgen production from these various sources, including the adrenal glands and the tumor itself, which can produce its own androgens even after testicular androgen suppression.
Other ARSIs directly block the androgen receptor (AR) on cancer cells. These drugs, known as androgen receptor antagonists, competitively bind to the AR, preventing testosterone and DHT from attaching and activating it. Beyond just blocking binding, these antagonists also inhibit the movement of the activated AR into the cell nucleus and its subsequent binding to DNA, which is necessary for stimulating cancer cell growth. This multi-faceted inhibition of AR signaling helps to overcome resistance mechanisms that can develop with traditional hormone therapies.
Indications for ARSI Treatment
Androgen Receptor Signaling Inhibitors (ARSIs) are prescribed for specific stages and conditions of prostate cancer, particularly when the disease has progressed or become resistant to initial hormone therapy. One primary indication is metastatic castration-resistant prostate cancer (mCRPC). This refers to prostate cancer that has spread and continues to grow despite very low testosterone levels, typically achieved through traditional androgen deprivation therapy (ADT). In this advanced stage, ARSIs help manage disease progression.
ARSIs are also used in non-metastatic castration-resistant prostate cancer (nmCRPC). In this scenario, the cancer is still growing, evidenced by rising prostate-specific antigen (PSA) levels, even with suppressed testosterone, but conventional imaging scans do not show spread. For patients with nmCRPC who have a rapidly rising PSA, ARSIs can delay metastases and prolong survival.
Furthermore, ARSIs have an expanding role in metastatic hormone-sensitive prostate cancer (mHSPC). This is when the cancer has spread beyond the prostate but still responds to hormone therapy. Combining ARSIs with traditional ADT in mHSPC can lead to improved overall survival and delayed cancer progression compared to ADT alone.
Common ARSI Medications and Management
Several common ARSI medications are used in prostate cancer treatment, each with a specific mechanism. Abiraterone acetate, often prescribed with prednisone, works by inhibiting the CYP17 enzyme, reducing androgen production from the adrenal glands and tumor cells. It is typically taken orally on an empty stomach. Enzalutamide, apalutamide, and darolutamide are other widely used ARSIs that directly block the androgen receptor on cancer cells, preventing hormone binding, nuclear translocation, and DNA interaction. These are also oral medications.
Like all medications, ARSIs can cause side effects. Common side effects across these agents include fatigue, hot flashes, and high blood pressure. Patients taking abiraterone acetate may also experience fluid retention and low potassium levels due to its effect on mineralocorticoid levels, which is why it is given with prednisone to help manage these effects.
Enzalutamide and apalutamide have been associated with musculoskeletal pain, rash, and an increased risk of falls and fractures. Enzalutamide can also carry a small risk of seizures. Darolutamide is noted for having lower central nervous system side effects, such as fatigue or seizures, compared to some other ARSIs, due to its limited ability to cross the blood-brain barrier.
Ongoing medical supervision is important during ARSI therapy. Doctors typically monitor prostate-specific antigen (PSA) levels regularly, as a decline in PSA often indicates treatment effectiveness. Regular follow-up appointments allow healthcare providers to assess for side effects, manage any emerging issues, and adjust treatment as needed.