Androgen Deprivation Therapy (ADT) is a foundational treatment for prostate cancer, a disease whose growth is primarily fueled by male sex hormones called androgens, most notably testosterone. ADT works by significantly reducing the level of testosterone in the body, effectively starving the cancer cells of the signal they need to multiply. This treatment causes the tumor to shrink or its progression to slow down considerably, resulting in a decline in the Prostate-Specific Antigen (PSA) level. The duration of ADT effectiveness varies widely among individuals, depending heavily on the specific characteristics of the patient’s disease.
Initial ADT Treatment Schedules
The duration of initial ADT is determined by the cancer stage and treatment goal. For localized or locally advanced disease receiving radiation, ADT is prescribed for a fixed duration. This is typically four to six months for intermediate-risk disease, or 24 to 36 months for high-risk disease. Extending the therapy duration in these settings can improve long-term outcomes for patients with aggressive characteristics.
For men with advanced or metastatic prostate cancer, ADT is often initiated as continuous therapy (CT), where hormone suppression is maintained indefinitely. CT is the standard approach because it provides the most consistent suppression of testosterone, maximizing the anti-cancer effect. However, intermittent therapy (IT) is sometimes used, involving cycles of “on-treatment” and “off-treatment” periods.
In intermittent therapy, ADT is administered until the PSA level drops to a very low point (nadir), and then treatment is paused. Therapy restarts when the PSA level rises back to a pre-determined threshold, such as 10 or 20 ng/mL. The rationale for IT is to provide breaks from side effects like fatigue and hot flashes, potentially improving quality of life. The duration of the “off” period is unpredictable, ranging from a few months to over a year.
Prognostic Indicators for Treatment Duration
Several factors related to the tumor’s biology and a patient’s initial response predict how long ADT will remain effective. The initial stage is a primary determinant; patients with disease spread to distant sites have a significantly shorter response duration compared to those with localized disease. Tumor aggressiveness, measured by the Gleason score, also plays a defining role. A higher Gleason score (8 to 10) suggests a more rapidly dividing cancer that is likely to develop resistance sooner.
The Prostate-Specific Antigen (PSA) level at the start of therapy and how quickly it drops are informative. A high baseline PSA level, for example above 50 ng/mL, is associated with a shorter duration of response before progression. Conversely, achieving a very low PSA nadir, often less than 0.2 ng/mL, predicts a much longer time until resistance develops.
The rate at which the PSA rises before treatment, known as the PSA doubling time (PSADT), is a powerful predictor. A short PSADT (less than three to nine months) indicates a fast-growing cancer that will likely become resistant more quickly. Patients whose PSA takes a longer time to reach its lowest point after starting ADT (longer time to nadir) tend to have a more durable response.
Defining and Recognizing Treatment Resistance
ADT effectiveness ends when the disease progresses to Castration-Resistant Prostate Cancer (CRPC). This occurs when cancer cells evolve mechanisms allowing them to grow despite castrate-level testosterone, defined as a serum level below 50 nanograms per deciliter. For most men with metastatic disease, this period of effectiveness lasts a median of 18 to 36 months, though this is highly variable.
Resistance develops because the cancer learns to bypass the need for external testosterone. Cancer cells may begin producing their own androgens or develop hypersensitivity to the low levels of testosterone remaining in the body. They can also activate entirely different signaling pathways to fuel their growth, making the initial hormone-blocking strategy ineffective.
Clinically, the transition to CRPC is recognized by specific criteria while the patient is actively receiving ADT. The most common sign is biochemical progression, defined by three consecutive rises in the PSA level, resulting in an absolute value of at least 2.0 ng/mL. This rising PSA must occur despite the patient maintaining castrate levels of testosterone.
CRPC diagnosis is also confirmed by radiographic progression. This includes the appearance of two or more new lesions on a bone scan or measurable growth of soft tissue tumors on CT or MRI. Recognizing these markers signals the need to switch treatment strategies.
Treatment Pathways After ADT Stops Working
Once Castration-Resistant Prostate Cancer is confirmed, the treatment pathway shifts to more intensive systemic approaches. The goal is to continue suppressing the androgen pathway while targeting the cancer cells’ new growth mechanisms. This often involves introducing novel hormonal agents, which are second-generation anti-androgen drugs.
Novel agents like abiraterone or enzalutamide further disrupt the androgen receptor signaling pathway. Abiraterone blocks an enzyme necessary for androgen production in the adrenal glands and tumor cells. Enzalutamide directly blocks the androgen receptor, extending the lives of men with CRPC.
Chemotherapy, most commonly docetaxel, is another established option used to treat CRPC, especially when the disease is rapidly progressing or causing significant symptoms. Chemotherapy agents work by killing fast-growing cells throughout the body, including the resistant prostate cancer cells.
Targeted Therapies
For patients with specific genetic mutations, such as in the BRCA genes, targeted therapies like PARP inhibitors may be introduced to exploit the cancer’s DNA repair defects.
Radioligand Therapy
In select cases, for men with metastatic disease visible on a PSMA-PET scan, radioligand therapy, such as radium-223, can be used. This delivers targeted radiation directly to the bone metastases.