How does Androgen Deprivation Therapy (ADT) treat metastatic prostate cancer in the bone?

How ADT Treats Metastatic Prostate Cancer in Bone

Androgen Deprivation Therapy (ADT) works by eliminating testosterone, which prostate cancer cells—including those that have metastasized to bone—require for growth and survival, thereby causing tumor regression and disease control. 1

Mechanism of Action

Androgen Dependency of Prostate Cancer

• Prostate cancer is fundamentally an androgen-driven malignancy, meaning cancer cells depend on testosterone and dihydrotestosterone for proliferation and survival 2, 3
• This androgen dependency persists even after cancer cells metastasize to bone, making systemic androgen suppression effective against skeletal metastases 4
• ADT achieves therapeutic effect by reducing testosterone to castrate levels (<50 ng/dL), which deprives cancer cells of the hormonal signals necessary for continued growth 1, 5

Methods of Testosterone Suppression

ADT can be achieved through two equivalent approaches 6:

• Medical castration: LHRH agonists (leuprolide, goserelin) or LHRH antagonists (degarelix) that suppress pituitary production of luteinizing hormone, thereby eliminating testicular testosterone production 1, 7
• Surgical castration: Bilateral orchiectomy that permanently removes the primary source of testosterone 1, 6

Clinical Effects on Bone Metastases

Disease Control Mechanisms

• Castrate levels of testosterone are typically achieved within 2-4 weeks of initiating medical ADT and are maintained throughout treatment 5
• Once testosterone suppression occurs, prostate cancer cells in bone metastases undergo apoptosis (programmed cell death) and growth arrest 3
• Successfully treated bone metastases can become negative on bone scans, accompanied by marked decreases in PSA levels 1

Important Clinical Caveat

• When initiating LHRH agonist therapy, an antiandrogen must be given for 3-4 weeks initially to prevent testosterone flare, which can temporarily worsen bone pain and other symptoms from metastases 6, 5
• This flare phenomenon occurs because LHRH agonists initially stimulate testosterone production before suppressing it 7
• LHRH antagonists like degarelix avoid this surge entirely and achieve faster testosterone suppression 7

Standard Treatment Approach for Metastatic Disease

First-Line Therapy

Continuous ADT is recommended as the standard first-line treatment for metastatic hormone-naïve prostate cancer 1, 6:

• Medical or surgical castration achieves equivalent efficacy 1, 6
• Castrate testosterone levels should be maintained continuously once initiated 1
• More than 90% of patients with castration-resistant disease have bone metastases, underscoring the importance of early and sustained androgen suppression 1

Enhanced Treatment Options

• ADT plus docetaxel chemotherapy is recommended as first-line treatment for metastatic hormone-naïve disease in men fit enough for chemotherapy, as this combination improves survival beyond ADT alone 1, 6
• Combined androgen blockade (medical castration plus antiandrogen) provides modest additional benefit but with increased toxicity 6, 2

Limitations and Disease Progression

Development of Castration Resistance

• Despite initial effectiveness, most patients develop castration-resistant prostate cancer (CRPC) with a median time of 14-30 months 1, 2
• When cancer becomes castration-resistant, castrate testosterone levels must still be maintained while adding additional therapies 1
• Resistance mechanisms include androgen receptor activation and autocrine/paracrine androgen synthesis within tumor cells themselves 1, 4

Treatment After Progression

For bone-predominant CRPC, additional options include 1:

• Abiraterone or enzalutamide (androgen synthesis inhibitors and receptor antagonists)
• Radium-223 for symptomatic bone metastases without visceral disease
• Docetaxel or cabazitaxel chemotherapy
• Bone-targeted therapies (denosumab or zoledronic acid) to prevent skeletal-related events

Critical Monitoring and Side Effects

Bone Health Concerns

• ADT causes significant bone loss and increased fracture risk because androgens are essential for maintaining bone mineral density in men 8
• Men on long-term ADT should undergo bone densitometry monitoring for osteoporosis 1
• Calcium and vitamin D supplementation is recommended for all patients on ADT with bone metastases 1

Response Monitoring

• Response to ADT should be monitored by measuring serum testosterone (confirming castrate levels <50 ng/dL) and PSA levels 5
• Bone scans can show a "flare phenomenon" after treatment initiation that mimics progression but actually represents healing—this should not be misinterpreted as treatment failure 1
• As bone metastases respond to treatment, they often become more densely sclerotic on CT, which can be falsely interpreted as progression 1