Prostate cancer arises from the uncontrolled growth of cells in the prostate gland, a small organ in men that contributes to semen production. A defining characteristic of prostate cancer is its reliance on male hormones, known as androgens, particularly testosterone, for growth and spread. Because of this dependency, a common initial treatment strategy involves hormone therapy, also called androgen deprivation therapy (ADT). This therapy aims to reduce the levels of androgens in the body or block their action on cancer cells, thereby slowing cancer growth or causing tumors to shrink.
Understanding Castration Resistance
Despite initial success with hormone therapy, prostate cancer cells can adapt and continue to grow even when androgen levels are significantly lowered; this is known as castration resistance. This means the cancer progresses despite very low or undetectable levels of testosterone, typically below 50 nanograms per deciliter (ng/dL).
The mechanisms behind this resistance are complex, often involving changes within the cancer cells themselves. One common adaptation is alterations in the androgen receptor, a protein that binds to androgens and signals cancer cells to grow. Cancer cells may produce more androgen receptors, making them more sensitive to minute amounts of remaining androgens, or the receptors might become activated by other non-androgen signals. Some prostate cancer cells can also develop the ability to produce their own androgens, creating an internal supply that fuels their growth despite external androgen deprivation. Additionally, alternative growth pathways, independent of the androgen receptor, can become activated, allowing the cancer to bypass androgen signaling.
Identifying CRPC Progression
CRPC progression is identified primarily through specific indicators. A rising Prostate-Specific Antigen (PSA) level is a significant sign, especially when it continues to increase despite ongoing hormone therapy that has successfully lowered testosterone to castrate levels. PSA is a protein produced by prostate tissue; elevated or rising levels indicate cancer activity. Generally, a rise of over 25% in PSA within two consecutive measurements, with an absolute value above 2.0 ng/mL, can suggest biochemical progression.
Beyond PSA levels, new metastases, or cancer spread to other body parts, on imaging scans confirms progression. Common imaging tests include computed tomography (CT) scans, magnetic resonance imaging (MRI), and bone scans, which can detect cancer spread to bones, lymph nodes, or other organs. If the cancer has spread to bones, patients might experience new or worsening bone pain, which can be a symptom.
Treatment Approaches for CRPC
Once prostate cancer becomes castration-resistant, therapeutic options are available to manage the disease. Second-generation androgen receptor pathway inhibitors, such as abiraterone acetate and enzalutamide, are often used. Abiraterone inhibits CYP17, an enzyme involved in androgen production in adrenal glands and tumor cells, further reducing androgen synthesis. Enzalutamide, on the other hand, directly blocks the androgen receptor, preventing androgens from binding and signaling cancer cell growth, and also inhibits the movement of the receptor into the cell nucleus and its binding to DNA.
Chemotherapy agents, such as docetaxel and cabazitaxel, also treat CRPC, particularly for symptomatic or aggressive disease. Docetaxel interferes with microtubules, structures important for cell division, leading to cancer cell death. Cabazitaxel functions similarly, disrupting microtubule networks and preventing cancer cells from dividing.
Radiopharmaceuticals, like radium-223, offer a targeted approach for CRPC that has spread to bones. Radium-223 mimics calcium and is selectively absorbed by areas of increased bone turnover, often sites of bone metastases. Once in the bone, it emits alpha particles, delivering localized radiation directly to cancer cells, causing DNA damage and cell death with minimal damage to healthy tissue.
Immunotherapy, exemplified by sipuleucel-T, is a unique treatment strategy. This therapy involves collecting a patient’s own immune cells, exposing them to a protein found in most prostate cancer cells, and then reinfusing them back into the patient. These activated immune cells recognize and attack prostate cancer cells throughout the body. Targeted therapies, such as PARP inhibitors like olaparib, are used for CRPC patients with specific genetic mutations, particularly in DNA repair genes like BRCA1 or BRCA2. These inhibitors block DNA repair enzymes, making cancer cells with existing DNA repair deficiencies more susceptible to damage and death.
Ongoing Management and Support
Living with CRPC requires continuous monitoring and a focus on maintaining quality of life. Regular surveillance of PSA levels and periodic imaging scans, such as CT and bone scans, are conducted to track disease progression and assess the effectiveness of ongoing treatments. This consistent monitoring helps the healthcare team make informed decisions about adjusting treatment strategies as needed.
Managing symptoms is a central aspect of care, particularly if the cancer has spread to bones, which can cause pain. Supportive care interventions, including pain management, nutritional support, and physical therapy, are often incorporated to alleviate symptoms and improve daily functioning. Involvement in clinical trials offers an opportunity to access new and experimental treatments that may not yet be widely available, contributing to the advancement of CRPC therapies. A multidisciplinary care team, typically including oncologists, urologists, radiation oncologists, pain specialists, and palliative care providers, works collaboratively to provide comprehensive and individualized care.