What is androgen deprivation therapy (ADT)?

Androgen Deprivation Therapy (ADT): Definition and Applications

Androgen deprivation therapy (ADT) is a treatment approach that prevents activation of androgen receptors in target cells through either reduction in testosterone production or androgen receptor blockade, used primarily for palliation in metastatic, recurrent, or progressive prostate cancer. 1

What is ADT?

ADT encompasses several therapeutic approaches that aim to reduce androgen activity:

1. Castration therapies - Treatments that decrease serum testosterone levels:

   • Surgical castration (bilateral orchiectomy) - Surgical removal of the testes
   • Medical castration - Using medications such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide) 1, 2

2. Antiandrogen therapies - Treatments that competitively inhibit androgen receptors:

   • Nonsteroidal antiandrogens - Block androgen receptors without steroidal effects
   • Steroidal antiandrogens - Block androgen receptors but have steroidal properties 1

3. Combined androgen blockade (CAB) - The combination of medical castration plus an antiandrogen 1

Mechanisms of Action

Different ADT approaches work through distinct mechanisms:

• LHRH agonists (like leuprolide): Initially stimulate the pituitary to release LH, but with continued administration, cause downregulation of receptors, leading to suppression of testosterone production 2

• Antiandrogens: Competitively inhibit the binding of testosterone and dihydrotestosterone to androgen receptors in the prostate 1

• CYP17 inhibitors (like abiraterone): Block the enzyme CYP17, which is required for androgen biosynthesis in testicular, adrenal, and prostatic tumor tissues 3

Clinical Applications of ADT

ADT is primarily used in:

• Metastatic prostate cancer - Standard first-line treatment
• Recurrent prostate cancer after primary therapy
• Progressive prostate cancer without distant metastases
• Locally advanced prostate cancer - Sometimes in combination with radiation therapy 1

Standard Treatment Options

The American Society of Clinical Oncology recommends:

• Bilateral orchiectomy or LHRH agonists as the initial treatment options for androgen-sensitive metastatic prostate cancer 1

• Nonsteroidal antiandrogens may be discussed as an alternative, though they are generally less effective than castration therapies 1

• Combined androgen blockade (adding nonsteroidal antiandrogen to castration therapy) may offer a small survival benefit but with increased toxicity 1

Side Effects and Considerations

ADT is associated with significant side effects that must be considered:

• Cardiovascular effects - Increased risk of myocardial infarction, sudden cardiac death, and stroke 2
• Metabolic effects - Hyperglycemia and increased risk of diabetes 2
• Bone health - Osteoporosis and increased fracture risk 4
• Sexual function - Impotence and decreased libido 4
• Body composition - Muscle weakness and increased fat mass 5
• QT interval prolongation - Potential for cardiac arrhythmias 2

Timing of ADT

The timing of ADT initiation remains controversial:

• Early ADT - Starting at diagnosis of metastatic or recurrent disease
• Deferred ADT - Waiting until clinical signs or symptoms appear 1

While early ADT may delay time to clinical metastases, there is limited evidence that it improves overall survival compared to deferred therapy in many patients 1.

Emerging Approaches

Recent advances in ADT include:

• Intermittent ADT - Cycles of treatment followed by treatment breaks, which may provide quality of life benefits while maintaining efficacy 1, 4

• Next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide, apalutamide, and darolutamide, which provide more comprehensive AR axis targeting 6

• Combination approaches - Adding chemotherapy or other targeted therapies to ADT for improved outcomes in specific patient populations 4, 6

Important Clinical Considerations

• ADT should be considered a palliative treatment for metastatic disease, with the goal of improving quality of life 1

• The relative efficacy of different ADT approaches appears small, but toxicity can be substantial, making shared decision-making between patients and physicians essential 1

• Patients receiving ADT should be monitored for cardiovascular disease, diabetes, bone health, and other potential complications 2

• For biochemical recurrence after local treatments, early hormonal therapy is not routinely advised but may be considered for those with short PSA doubling time 1

ADT remains the cornerstone of treatment for advanced prostate cancer, with ongoing research focused on optimizing its use and developing strategies to delay or overcome resistance.