What is the best treatment for a patient in good health with increasing metastatic castration-resistant prostate cancer?

Treatment of Metastatic Castration-Resistant Prostate Cancer in Good Health Patients

For a patient in good health with increasing metastatic castration-resistant prostate cancer, the best treatment is abiraterone plus prednisone or enzalutamide as first-line therapy, with continuation of androgen deprivation therapy indefinitely. 1, 2

Continue Androgen Deprivation Therapy

• Androgen deprivation therapy (ADT) must be continued indefinitely regardless of any additional therapies added. 1, 3, 2
• Verify serum testosterone remains <50 ng/dL before diagnosing castration resistance and throughout treatment. 1, 3
• All novel therapies for mCRPC are studied and approved with concurrent ADT as the backbone—castration-resistant disease does not mean androgen-independent disease. 3

First-Line Treatment Selection Based on Symptom Status

For Asymptomatic or Minimally Symptomatic Patients

Preferred options (Category 1):

• Abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily demonstrates improved overall survival (OS), quality of life, and favorable benefit-harm balance. 1, 2
• Enzalutamide 160 mg daily demonstrates improved OS, quality of life, and favorable benefit-harm balance. 1, 2
• Both agents have strong evidence (evidence strength: strong; recommendation strength: strong). 1

Alternative option:

• Sipuleucel-T may be offered to asymptomatic or minimally symptomatic patients, with median OS of 30.7 months, though it has unclear quality of life impact. 1, 4
• Sipuleucel-T should not be used in patients with visceral metastases as benefit has not been demonstrated in this population. 4

For Symptomatic Patients with Good Performance Status

Preferred options:

• Docetaxel 75 mg/m² intravenously every 3 weeks plus prednisone 5 mg orally twice daily improves OS (median 19.2 months), disease control, symptom palliation, and quality of life. 1, 5
• Abiraterone plus prednisone or enzalutamide should also be offered as they demonstrate moderate benefit with low toxicity. 1
• Radium-223 should be offered to patients with symptomatic bone metastases without known visceral disease. 1

Triplet Therapy Consideration

• For patients with high-volume disease who are fit for chemotherapy, triplet therapy with ADT plus docetaxel plus either abiraterone or darolutamide improves OS over ADT with docetaxel alone (Category 1, preferred). 1
• The PEACE-1 trial demonstrated that ADT plus docetaxel plus abiraterone resulted in improved radiographic progression-free survival (HR 0.50) and OS (HR 0.75) compared to ADT plus docetaxel alone. 1

Second-Line Treatment After Progression

After First-Line ARPI (Abiraterone or Enzalutamide)

• Docetaxel 75 mg/m² every 3 weeks plus prednisone is recommended for patients who received prior ARPI. 2
• Continue ADT throughout all treatment lines. 3, 2

After Docetaxel Chemotherapy

For patients with good performance status:

• Abiraterone plus prednisone, cabazitaxel, or enzalutamide should be offered (Standard recommendation). 1, 2
• If the patient received abiraterone plus prednisone prior to docetaxel, they should be offered cabazitaxel or enzalutamide. 1
• 177Lu-PSMA-617 is recommended for patients with PSMA-positive disease on PET imaging who received prior ARPI and taxane chemotherapy. 6, 2
• Cabazitaxel 25 mg/m² every 3 weeks may be offered with moderate benefit but moderate to high toxicity risk. 1, 2

Special Population Considerations

Patients with BRCA1/2 Alterations

• For BRCA1/2-positive patients who did not receive prior ARPI: combination of PARP inhibitor with ARPI (talazoparib plus enzalutamide, or olaparib/niraparib plus abiraterone) is recommended. 2
• For BRCA1/2-positive patients who received prior ARPI: olaparib monotherapy showed OS benefit. 2
• Early adoption of somatic genetic testing is recommended to identify these patients. 2

Patients with Bone Metastases

• All patients with mCRPC and bony metastases should receive a bone-protective agent (zoledronic acid or denosumab). 2
• Zoledronic acid 4 mg every 3-4 weeks is the only bisphosphonate with proven clinical benefit in reducing skeletal complications in hormone-refractory prostate cancer. 1

Survival Expectations with Modern Therapy

• Asymptomatic, chemotherapy-naïve patients with good performance status can expect median survival of 30-35+ months with modern ARPI therapy. 4
• Patients receiving sequential multiple lines of therapy can often achieve 5+ years of survival. 4
• With modern therapies, many patients now live 5 or more years, compared to less than 2 years in the pre-2004 era. 4

Critical Pitfalls to Avoid

• Never discontinue ADT even when adding novel therapies—maintaining castrate testosterone levels is essential for optimal outcomes. 3, 2
• Do not delay treatment transitions as this can negatively impact overall survival. 4
• Do not administer docetaxel to patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN due to increased risk of severe toxicity and treatment-related mortality. 5
• Do not administer docetaxel to patients with neutrophil counts <1500 cells/mm³. 5
• Avoid estramustine due to increased risk of clinically important toxicities without evidence of improved survival. 1
• Do not offer sipuleucel-T to symptomatic patients as it is only indicated for asymptomatic or minimally symptomatic disease. 1

Palliative Care Integration

• Palliative care should be offered to all patients with mCRPC from the time of diagnosis, not just at end of life. 1, 2
• Symptom control should be optimized throughout treatment. 1