Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs when prostate cancer progresses despite standard hormone therapy, known as androgen deprivation therapy (ADT). ADT lowers the body’s testosterone to castrate levels, starving the cancer cells. The “castration-resistant” term means the cancer is growing even with these low hormone levels, typically signaled by a rising Prostate-Specific Antigen (PSA) blood test result. The “non-metastatic” designation means conventional imaging tests, such as CT scans and bone scans, show no evidence that the cancer has spread. The primary objective of treatment at this stage is to control the disease and delay the onset of metastasis.
Understanding Castration Resistance and Treatment Goals
Prostate cancer cells initially rely on androgens, like testosterone, to fuel their growth through the androgen receptor (AR) pathway. ADT works by cutting off the primary supply of testosterone, but the cancer cells eventually adapt to this low-androgen environment, leading to castration resistance. This adaptive process involves several complex mechanisms that allow the cancer cells to keep the AR pathway active.
Cancer cells achieve resistance by producing their own androgens within the tumor or by increasing the number of androgen receptors on the cell surface, making them hypersensitive to even trace amounts of circulating hormones. Other mechanisms include the development of truncated AR variants that are active even without hormone binding. Since the AR pathway remains the main driver of growth, treatment focuses on shutting down this pathway further.
Androgen Receptor Axis Inhibitors (ARAIs) are a class of treatments designed to target this adapted pathway. These agents work by binding to the androgen receptor, effectively blocking the remaining androgens from binding. This inhibition also prevents the AR from moving into the cell nucleus, where it would bind to DNA and trigger cancer cell growth.
By blocking the adapted AR pathway, ARAIs aim to stop the cancer from growing and progressing. The primary goal of treatment in nmCRPC is to extend metastasis-free survival (MFS), which is the time until the cancer is detected as having spread to other parts of the body. Delaying the development of metastatic disease is considered a therapeutic benefit in this stage.
Specific Androgen Receptor Axis Inhibitors for nmCRPC
Three oral medications are currently approved by the FDA for nmCRPC, all belonging to the ARAI drug class. These treatments—apalutamide, enzalutamide, and darolutamide—have demonstrated success in delaying progression to metastatic disease. The availability of these options allows for a personalized approach, considering a patient’s overall health and potential side effect profile.
Apalutamide (Erleada) is a second-generation AR inhibitor. It works by blocking the binding of androgens to the receptor and preventing the receptor’s movement to the cell nucleus. In the SPARTAN clinical trial, apalutamide prolonged the median MFS compared to placebo. Patients typically take this medication once daily, and its effectiveness is strong in men with a rapidly rising PSA level, often defined by a PSA doubling time of ten months or less.
Enzalutamide (Xtandi) is another second-generation AR inhibitor that disrupts the AR signaling pathway. The PROSPER trial established its efficacy in nmCRPC, showing improvement in MFS for patients treated with the drug. This medication is taken once daily and has a proven track record of reducing the risk of metastasis or death.
Darolutamide (Nubeqa) is the third approved agent in this class. Results from the ARAMIS trial demonstrated that darolutamide extended median MFS, delaying the time to metastasis. Darolutamide is unique because it has a lower propensity to cross the blood-brain barrier, which translates to a more favorable profile of central nervous system-related side effects. This medication is typically administered twice daily.
Managing Treatment and Monitoring Progress
While ARAIs are effective in controlling nmCRPC, the treatment involves managing potential side effects that can affect a patient’s quality of life. Common side effects across the class include fatigue and an increased risk of falls and fractures. Cardiovascular issues, such as high blood pressure, may also occur with these medications.
Specific agents have distinct side effect profiles that influence treatment choice. Enzalutamide and apalutamide can be associated with a higher risk of central nervous system effects, including dizziness, mental impairment, and in rare cases, seizures. Management strategies for these side effects include physical therapy to address balance and strength, and regular blood pressure monitoring and medication.
Adherence to the daily oral medication schedule is important to maintain therapeutic drug levels and ensure the cancer remains controlled. Patients should also be monitored for potential drug-drug interactions, as some ARAIs can affect the metabolism of other medications. Regular monitoring involves periodic blood tests to track PSA levels.
A rising PSA level is the first sign of progression, and a shorter PSA doubling time indicates a higher risk of metastasis. In addition to blood tests, patients undergo periodic imaging, such as CT and bone scans, to confirm that the cancer remains non-metastatic. If imaging shows evidence of spread, the diagnosis changes to metastatic castration-resistant prostate cancer, and the treatment plan is adjusted accordingly.