Castration-resistant prostate cancer (CRPC) is a form of prostate cancer that continues to progress despite treatments designed to lower testosterone levels. While many early-stage prostate cancers rely on testosterone to grow, CRPC develops the ability to grow even in environments with low testosterone. This advanced stage of prostate cancer presents challenges in management due to its persistent growth.
Initial Prostate Cancer Treatment and Hormone Sensitivity
Prostate cancer begins when abnormal cells develop and multiply in the prostate gland, a small gland in the male reproductive system that contributes to semen production. These cancerous cells often depend on male hormones, such as testosterone, for their growth. This dependence makes them “hormone-sensitive.”
The initial treatment strategy for prostate cancer that has spread or is at high risk of recurrence often involves hormone therapy, specifically androgen deprivation therapy (ADT). ADT works by reducing the levels of androgens or by blocking their action on prostate cancer cells. This can be achieved through medications that stop the testicles from producing testosterone or by surgical removal of the testicles, lowering testosterone levels. By depriving the cancer cells of their primary fuel, ADT can shrink tumors and slow down their growth.
The Mechanisms of Resistance
Despite the initial effectiveness of ADT, prostate cancer cells can adapt over time, leading to the development of castration-resistant prostate cancer. Several mechanisms contribute to this acquired resistance.
One common mechanism involves changes to the androgen receptor (AR). Cancer cells may increase the number of androgen receptors on their surface or develop mutations. This “androgen receptor overexpression” makes the cells hypersensitive, allowing them to respond to even very low levels of circulating androgens that remain after ADT. Some mutations can also cause the AR to become “promiscuous,” meaning it can be activated by other hormones or even by certain anti-androgen drugs.
Cancer cells can also activate “bypass pathways” that allow them to grow independently of the androgen receptor. This involves the activation of alternative signaling routes that can stimulate AR activity or promote cell growth directly. These pathways enable the cancer cells to circumvent the need for androgens.
Another resistance mechanism involves the cancer cells’ ability to produce their own androgens or convert other hormones into testosterone. While the testicles are the primary source of testosterone, the adrenal glands and even prostate cancer cells themselves can produce androgen precursors. These precursors can then be converted into more potent androgens like dihydrotestosterone (DHT) within the tumor microenvironment, providing the cancer cells with a local supply of growth-promoting hormones despite systemic testosterone suppression.
Identifying Castration-Resistant Prostate Cancer
Doctors diagnose castration-resistant prostate cancer when the disease shows signs of progression despite consistently low testosterone levels, typically below 50 nanograms per deciliter, achieved through ADT. The primary indicator of this progression is a rising Prostate-Specific Antigen (PSA) level. An increase in PSA blood levels signals that the cancer is growing again.
Beyond blood tests, imaging studies are also used to identify disease progression. These may include computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, and bone scans. These imaging techniques help determine if the cancer has spread to other parts of the body, such as lymph nodes or bones, or if existing tumors have grown larger. Newer molecular imaging techniques are also being used to detect progression more accurately.
Treatment Strategies
Treatment for castration-resistant prostate cancer focuses on controlling disease progression, managing symptoms, and improving a patient’s quality of life. Patients typically continue ADT to maintain low testosterone levels, as this can still help control some cancer cells.
Next-generation hormonal therapies are important in CRPC treatment. Medications like abiraterone and enzalutamide work differently from initial ADT by either blocking androgen production from other sources, such as the adrenal glands, or by more effectively inhibiting the androgen receptor’s function. These oral drugs can extend life and are often used both before and after chemotherapy.
Chemotherapy, often with drugs such as docetaxel or cabazitaxel, is another treatment option, particularly for metastatic CRPC causing symptoms. These drugs aim to destroy cancer cells or slow their growth. Chemotherapy may be given with prednisone, a corticosteroid.
Targeted therapies, such as PARP inhibitors, are used for CRPC patients with specific genetic mutations, particularly in DNA repair genes. These inhibitors prevent cancer cells from repairing their damaged DNA, leading to cell death. Radiopharmaceuticals are also available for CRPC that has spread to the bones, delivering radiation directly to bone metastases to relieve pain and potentially extend survival.
Immunotherapy is a personalized treatment that uses a patient’s own immune cells to fight prostate cancer. This therapy is used for patients with metastatic CRPC who have few or no symptoms. Symptom management, including pain control with various medications and bone-strengthening agents, is an important aspect of comprehensive care for CRPC patients.