What is the recommended treatment for metastatic hormone-sensitive prostate cancer?

Treatment for Metastatic Hormone-Sensitive Prostate Cancer

For metastatic hormone-sensitive prostate cancer, the recommended treatment is ADT (androgen deprivation therapy) combined with intensification using either an androgen receptor pathway inhibitor (abiraterone, apalutamide, enzalutamide, or darolutamide) or docetaxel chemotherapy, with triplet therapy (ADT + androgen receptor inhibitor + docetaxel) providing the greatest survival benefit for fit patients with high-volume or high-risk disease. 1, 2

First-Line Treatment Approach

Triplet Therapy (Preferred for Fit Patients)

ADT + docetaxel + darolutamide is the most effective regimen, demonstrating superior overall survival with HR 0.68 (95% CI 0.57-0.80) in the ARASENS trial, particularly beneficial in patients with de novo disease (HR 0.71) and high-volume disease (HR 0.69). 1, 2

• ADT + docetaxel + abiraterone + prednisone is also highly effective (HR 0.75,95% CI 0.59-0.95 in PEACE-1 trial), especially for patients with multiple bone metastases (>3) or visceral metastases. 1, 2

• Docetaxel should be administered at 75 mg/m² every 3 weeks for six cycles when used in combination regimens. 3

Doublet Therapy (Alternative for Patients Unable to Tolerate Triplet)

When triplet therapy is not feasible, ADT combined with a novel hormonal agent provides substantial survival benefit:

• ADT + abiraterone + prednisone (ESMO-MCBS score: 4) 1
• ADT + apalutamide (ESMO-MCBS score: 4) 1
• ADT + enzalutamide (ESMO-MCBS score: 4) 1, 4
• ADT + darolutamide 1

All four androgen receptor pathway inhibitors demonstrate comparable efficacy, with benefit-harm assessments showing >60% probability of net clinical benefit for abiraterone, enzalutamide, and apalutamide. 5

ADT Backbone Options

Bilateral orchiectomy or LHRH agonists are the standard ADT methods, with both providing equivalent testosterone suppression. 1, 6

• When initiating LHRH agonist therapy, administer an antiandrogen for 3-4 weeks initially to prevent testosterone flare. 6
• LHRH agonists should be continued throughout treatment for castration-resistant disease or metastatic castration-sensitive disease. 4

Treatment Selection Algorithm

For Fit Patients with High-Volume Disease

High-volume disease is defined as ≥4 bone metastases with ≥1 beyond vertebral bodies/pelvis, or visceral metastases.

• First choice: ADT + docetaxel + darolutamide or ADT + docetaxel + abiraterone + prednisone 1, 2
• Alternative if chemotherapy contraindicated: ADT + androgen receptor pathway inhibitor (abiraterone, apalutamide, enzalutamide, or darolutamide) 1

For Patients with Low-Volume Disease

• ADT + androgen receptor pathway inhibitor is appropriate, as survival benefits are maintained across volume subgroups. 1, 5
• Triplet therapy may still be considered for high-risk features (Gleason score 8-10, rapid PSA doubling time). 2

For Vulnerable/Frail Patients

ADT monotherapy should only be used in vulnerable patients who cannot tolerate treatment intensification, as it provides inferior survival compared to combination approaches. 1

Combined Androgen Blockade Considerations

Combined androgen blockade (CAB = medical castration + antiandrogen) provides modest survival benefit with 1-5% absolute mortality reduction at 5 years, but increases toxicity. 1, 3

• Patients willing to accept increased toxicity for small survival gains may be offered nonsteroidal antiandrogen addition to castration therapy. 1
• Steroidal antiandrogens should not be offered as monotherapy. 1
• Nonsteroidal antiandrogen monotherapy may be discussed as an alternative with potentially more favorable side-effect profile. 1

Continuous vs. Intermittent ADT

Continuous ADT is recommended over intermittent ADT for metastatic disease, as the only adequately powered phase 3 trial (SWOG-9346) demonstrated inferior survival with intermittent therapy. 6, 3, 7

• Intermittent ADT remains experimental and should only be used within clinical trials. 1

Quality of Life Considerations

ADT + docetaxel causes short-term HRQoL decline lasting 3-6 months, while ADT + abiraterone may provide HRQoL benefit up to 24 months compared to ADT alone. 5

• ADT + enzalutamide, apalutamide, or darolutamide show no significant HRQoL difference versus ADT alone, making them preferable to docetaxel-containing regimens when HRQoL is prioritized. 5
• Regular exercise reduces fatigue and improves quality of life in men on ADT. 6, 3

Monitoring Requirements

• PSA measurements every 3-4 weeks initially to assess treatment response. 8, 3
• Regular imaging with CT scans and bone scintigraphy to assess disease status. 8, 3
• Monitor for adverse effects specific to each agent, including seizure risk with enzalutamide (0.6% overall, 2.2% in predisposed patients). 4

Critical Pitfalls to Avoid

Do not use ADT monotherapy in fit patients with metastatic disease, as this represents suboptimal care with substantially inferior survival outcomes—real-world data shows 76.1% of mHSPC patients receive non-guideline-concordant care. 9

• Do not delay treatment intensification while waiting for symptoms, as immediate combination therapy provides superior outcomes. 1, 2
• Do not forget testosterone flare prophylaxis when starting LHRH agonists. 6
• Ensure proper swallowing assessment when prescribing enzalutamide, as severe dysphagia or choking can occur; consider smaller tablet sizes or discontinue if swallowing difficulty persists. 4