Prostate cancer is one of the most common malignancies diagnosed in men, and its growth is primarily driven by male hormones called androgens. Since the 1940s, therapy has focused on reducing the body’s androgen levels, causing tumors to shrink or stop growing. This approach targets the tumor’s dependence on hormones. Androgen Receptor Signaling Inhibitors (ARSIs) represent a major advancement in this targeted therapy, offering a powerful way to disrupt this growth pathway. These medications have significantly improved outcomes for patients across various stages of the disease.
The Role of Androgen Signaling in Prostate Cancer Growth
The growth of both normal prostate cells and prostate cancer cells is heavily reliant on androgens, such as testosterone and dihydrotestosterone (DHT). These hormones are produced mainly by the testes, with the adrenal glands and the tumor itself contributing smaller amounts. Once produced, androgens travel through the bloodstream to prostate cells.
Inside the cell, the androgen acts as a signal that connects with the Androgen Receptor (AR). When the androgen binds to the AR, the receptor activates and moves into the cell’s nucleus. This activated AR then binds to the cell’s DNA, turning on genes that promote cell division and survival. Prostate cancer cells hijack this natural signaling mechanism to proliferate and grow. Disrupting this cycle is the core principle of initial treatment for hormone-sensitive prostate cancer.
Defining Androgen Receptor Signaling Inhibitors
Androgen Receptor Signaling Inhibitors are a class of oral medications specifically designed to block the androgen-AR pathway, thereby starving the cancer cells of the necessary growth signal. These inhibitors achieve their effect through two distinct mechanisms, which define the primary types of ARSIs.
One type consists of Androgen Synthesis Inhibitors, which target the production of androgens themselves. The drug Abiraterone acetate (Zytiga) works by inhibiting the enzyme CYP17A1, required for androgen synthesis in the testes, adrenal glands, and tumor tissue. This action reduces the overall levels of testosterone and other androgens available to fuel cancer growth.
The second type of ARSI is the Androgen Receptor Antagonist, also known as a novel anti-androgen. These drugs, including Enzalutamide (Xtandi), Apalutamide (Erleada), and Darolutamide (Nubeqa), function by directly blocking the AR protein. They bind to the receptor, preventing the natural androgen from attaching and activating the growth signal. These antagonists also stop the AR from moving into the cell nucleus and inhibit its ability to bind to DNA, providing a triple-action block on the signaling pathway. Structural differences among the antagonists, such as Darolutamide’s lower penetration of the central nervous system, can lead to variations in their side effect profiles.
Clinical Application of ARSIs in Treatment Protocols
The introduction of ARSIs has fundamentally changed the treatment landscape for prostate cancer across multiple stages of the disease. Their use is no longer reserved only for late-stage disease but has been moved up to earlier phases to maximize therapeutic benefit.
In Metastatic Hormone-Sensitive Prostate Cancer (mHSPC), where the cancer has spread but still responds to hormone therapy, ARSIs are now used upfront in combination with traditional Androgen Deprivation Therapy (ADT). This combination, often called treatment intensification, is a standard first-line approach. The goal in mHSPC is to control disease progression, extend survival, and delay the transition to a more aggressive state.
When the disease progresses despite low testosterone levels, it is classified as Castration-Resistant Prostate Cancer (CRPC). ARSIs are used in patients with non-metastatic CRPC (nmCRPC) to delay the spread of the cancer. Drugs like Enzalutamide, Apalutamide, and Darolutamide are approved for this setting to extend the time patients live without developing detectable metastasis.
For patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC), ARSIs are a primary systemic treatment option after the cancer has progressed on initial ADT. At this stage, cancer cells have adapted to low androgen levels, often by increasing the number of ARs or synthesizing their own androgens. ARSIs are effective because they provide a more complete blockade of the AR signaling axis than previous hormone therapies.
Managing Potential Drug Effects
ARSIs are associated with a range of potential drug effects that require careful monitoring and management. The most commonly reported effects across the class include fatigue and hot flashes, which are experienced due to the profound reduction in androgen signaling.
For the synthesis inhibitor Abiraterone, there is a risk of hypertension, low potassium levels (hypokalemia), and fluid retention due to a secondary effect on other hormones. Abiraterone must be given in combination with a steroid like prednisone to counteract these mineralocorticoid effects. Liver function must also be monitored closely for signs of hepatotoxicity.
The receptor antagonists (Enzalutamide, Apalutamide, Darolutamide) have distinct profiles, with some showing a higher risk of cardiovascular events and falls. Enzalutamide has been associated with a low risk of seizures and a higher risk of high blood pressure compared to other ARSIs, necessitating close blood pressure monitoring. Darolutamide is structurally different and has less penetration into the brain, which may contribute to a lower incidence of central nervous system-related effects like seizures.