What are the first-line treatment options for a patient with metastatic castration-sensitive prostate cancer (CSPC), considering overall survival (OS) and progression-free survival (PFS)?

First-Line Treatment Options for Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Primary Recommendation

All patients with metastatic castration-sensitive prostate cancer should receive androgen deprivation therapy (ADT) combined with either a second-generation androgen receptor pathway inhibitor (apalutamide, enzalutamide, or abiraterone) or docetaxel chemotherapy, as these combinations significantly improve overall survival compared to ADT alone. 1, 2

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Standard Treatment Combinations with Survival Data

Apalutamide + ADT (TITAN Trial)

• Overall Survival (OS): Median not reached vs. 52.2 months with placebo (HR 0.65; 95% CI 0.53-0.79; P<0.001) 1, 2
• Progression-Free Survival (PFS): Median not reached vs. 22.1 months (HR 0.48; 95% CI 0.39-0.60; P<0.0001) 1, 2
• Dosing: 240 mg orally once daily with continuous LHRH agonist/antagonist 1, 2
• Study Design: Multicenter, randomized, double-blind, placebo-controlled phase III trial (N=1,052) 2
• Key Limitations: Common adverse events include rash (28%), hypothyroidism, and ischemic heart disease requiring monitoring 1
• Patient Population: Effective across all disease volumes (high and low), all Gleason scores, and with or without prior docetaxel 1, 2

Enzalutamide + ADT (ENZAMET/ARCHES Trials)

• Overall Survival: Improved OS with HR approximately 0.67-0.70 in pooled analyses 3
• Progression-Free Survival: Significant improvement across all subgroups 4
• Dosing: 160 mg orally once daily 5
• Study Design: Multiple phase III randomized controlled trials 5
• Key Limitations: Fatigue, seizure risk (rare), and cardiovascular events require monitoring 6
• Approval Status: FDA approved for mCSPC in December 2019 5

Abiraterone + Prednisone + ADT (LATITUDE/STAMPEDE Trials)

• Overall Survival: Demonstrated improved OS over ADT alone in high-risk disease 5, 4
• Progression-Free Survival: Significant PFS benefit particularly in high-volume/high-risk patients 4
• Dosing: Abiraterone 1000 mg daily plus prednisone 5 mg twice daily 7
• Study Design: Phase III randomized controlled trials 5
• Key Limitations: Mineralocorticoid excess (hypertension, hypokalemia, fluid retention), hepatotoxicity requiring monitoring 5
• Approval Status: FDA approved for mCSPC in February 2018 5

Docetaxel + ADT (CHAARTED/STAMPEDE Trials)

• Overall Survival:
  • CHAARTED: Median 57.6 vs. 47.2 months (HR ~0.72) in high-volume disease 4
  • Less clear benefit in low-volume disease 4, 3
• Progression-Free Survival: Improved PFS particularly in high-volume disease 4
• Dosing: 75 mg/m² IV every 3 weeks for up to 6 cycles 5, 6
• Study Design: Phase III randomized controlled trials 4
• Key Limitations:
  • Acute toxicity: neutropenia, febrile neutropenia, fatigue, neuropathy 5
  • Requires fitness for chemotherapy 6
  • Time-limited treatment (6 cycles) vs. continuous therapy with ARPIs 4

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Comparative Effectiveness

Network meta-analysis demonstrates that androgen receptor pathway inhibitors (ARPIs) provide superior overall survival compared to docetaxel (OS-HR 0.78; 95% CI 0.67-0.91), making ARPIs the preferred first-line intensification strategy when available. 3

• Pooled OS-HR for all intensification strategies vs. ADT alone: 0.69 (95% CI 0.61-0.78) 3
• ARPIs show consistent benefit across all disease volumes (high and low) 1, 4
• Docetaxel benefit most pronounced in high-volume disease 4, 3

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Treatment Selection Algorithm

For All Patients:

1. Verify castrate testosterone levels (<50 ng/dL) are achieved and maintained throughout treatment 5, 6
2. Continue ADT indefinitely regardless of additional therapies 5, 7

Preferred First-Line Approach:

• Apalutamide 240 mg daily + ADT (Category 1 recommendation, strongest survival data across all subgroups) 1, 2
• Alternative ARPIs: Enzalutamide 160 mg daily + ADT or Abiraterone 1000 mg daily + prednisone 5 mg BID + ADT 5, 1
• Selection among ARPIs should be guided by cost and patient-specific tolerability 1

Docetaxel 75 mg/m² q3weeks + ADT Reserved For:

• Patients unable to access or afford ARPIs 6
• High-volume disease when ARPIs contraindicated 4
• Patients preferring time-limited therapy (6 cycles) 4

High-Volume Disease Definition:

• Visceral metastases OR ≥4 bone lesions with ≥1 beyond vertebral bodies/pelvis 4

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Critical Pitfalls to Avoid

• Never delay intensification until symptoms develop—early initiation with metastatic disease improves survival 1
• Never use first-generation antiandrogens (bicalutamide, flutamide) as alternatives to second-generation ARPIs—they provide inferior survival outcomes 1
• Never assume lack of benefit in low-volume disease with ARPIs—TITAN and ENZAMET showed benefit across all volumes 1, 4
• Never discontinue ADT when adding intensification therapy—castration must be maintained indefinitely 5, 7
• Never repeat the same therapy after progression except docetaxel rechallenge after ARPI progression in select cases 5

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Bone Health and Supportive Care

• Zoledronic acid 4 mg IV annually or alendronate 70 mg PO weekly recommended when fracture risk warrants treatment 5
• Supplemental calcium 1200 mg daily and vitamin D3 800-1000 IU daily for all men >50 years on ADT 5
• Screen for and manage cardiovascular disease and diabetes—GnRH agonists increase risk of myocardial infarction, stroke, and metabolic complications 6

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Subsequent Therapy After Progression

After progression on first-line ARPI + ADT (without prior docetaxel), docetaxel chemotherapy becomes the preferred next option due to cross-resistance between ARPIs. 5, 7

• Switching from one ARPI to another after progression is rarely effective 5, 7
• Cabazitaxel reserved for post-docetaxel progression 7, 8
• Continue ADT throughout all subsequent lines of therapy 5, 7