How to treat metastatic castration-resistant prostate cancer (mCRPC) with [TREATMENT] and [MEDICATION]?

Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Continue Androgen Deprivation Therapy Indefinitely

All patients with mCRPC must continue lifelong androgen deprivation therapy (ADT) regardless of any additional systemic therapies added. 1, 2 Verify serum testosterone remains <50 ng/dL before diagnosing castration resistance and throughout all subsequent treatment lines. 2

First-Line Treatment Selection Based on Clinical Status

For Asymptomatic or Minimally Symptomatic Patients with Good Performance Status

Offer abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily (Category 1, preferred) or enzalutamide 160 mg daily as first-line therapy. 1, 2 Both agents demonstrate:

• Improved overall survival (median 30-35+ months in chemotherapy-naïve patients) 2
• Enhanced quality of life 1, 2
• Favorable benefit-harm balance 2

Alternative first-line options include: 1

• Darolutamide (Category 1, preferred for M0 CRPC with PSADT ≤10 months) 1
• Apalutamide 1
• Sipuleucel-T immunotherapy (only for asymptomatic/minimally symptomatic disease; rarely produces PSA decline or radiographic response) 1
• Docetaxel 75 mg/m² every 3 weeks with prednisone (Category 1) 1

For Symptomatic Patients with Good Performance Status

Offer docetaxel 75 mg/m² every 3 weeks plus prednisone as the standard first-line therapy. 1 This regimen provides:

• Median overall survival of 18.9 months (vs 16.5 months with mitoxantrone) 1
• Bone pain response in 35% of patients 1
• Quality of life improvements 1

Alternative dosing: Docetaxel 50 mg/m² every 2 weeks may offer improved tolerability with similar or better efficacy (median OS 19.5 vs 17.0 months), with lower febrile neutropenia rates (4% vs 14%). 1

For symptomatic bone metastases without visceral disease, offer radium-223 dichloride (50 kBq/kg IV every 4 weeks for 6 cycles). 1 This provides:

• Improved median survival (14.9 vs 11.3 months; HR 0.695) 1
• Delayed time to first skeletal-related event (15.6 vs 9.8 months) 1
• Low rates of grade 3-4 hematologic toxicity (neutropenia 2.2%, thrombocytopenia 6.3%) 1

For Symptomatic Patients with Poor Performance Status

Offer abiraterone/prednisone or enzalutamide as preferred options over chemotherapy. 1 While clinical trials primarily enrolled good performance status patients, these oral agents have acceptable safety profiles for poor performance status patients, especially when poor status is cancer-related rather than from comorbidities. 1

Alternative options include: 1

• Ketoconazole 400 mg three times daily with hydrocortisone (if abiraterone unavailable; 50% achieve >50% PSA decline, but higher toxicity) 1
• Radium-223 (if symptomatic bone metastases without visceral disease and poor performance directly related to bone pain) 1
• Mitoxantrone (palliative benefit only; no survival advantage) 1

Do not offer docetaxel or immunotherapy to poor performance status patients unless performance status is directly cancer-related and likely to improve with treatment. 1

Triplet Therapy for High-Volume Disease

For chemotherapy-fit patients with high-volume metastatic disease, offer triplet therapy: ADT plus docetaxel plus either abiraterone or darolutamide (Category 1, preferred). 2 This combination improves overall survival compared to ADT with docetaxel alone. 2

Bone Health Management

All patients with mCRPC and bone metastases should receive bone-protective agents: 2

• Zoledronic acid 4 mg IV every 3-4 weeks (only bisphosphonate with proven clinical benefit in reducing skeletal complications) 2
• Denosumab 120 mg subcutaneously every 4 weeks (alternative option) 2

Ensure adequate calcium and vitamin D supplementation (vitamin D 700-800 IU/day shows fracture reduction; 400 IU/day ineffective). 1 Monitor for hypocalcemia, especially with denosumab (5% risk of osteonecrosis of jaw). 1

Second-Line Treatment After Progression

After First-Line Novel Androgen Receptor-Directed Therapy (ARDT)

If progressed on abiraterone, switch to enzalutamide, or vice versa (though cross-resistance is common; PSA response rates ~20-22% with modest PSA-PFS of 2.9 months). 3 Back-to-back use of abiraterone and enzalutamide is common in clinical practice despite limited efficacy. 4

Alternative strategy after abiraterone/prednisone progression: Switch prednisone to dexamethasone 0.5 mg daily while continuing abiraterone. 1 This achieves:

• PSA decline ≥30% in 46% of patients 1
• Median PFS of 10.35 months 1
• Minimal toxicity (no grade 3-4 events reported) 1

After First-Line Docetaxel

Offer abiraterone 1000 mg daily plus prednisone 5 mg twice daily (median OS 15.8 vs 11.2 months vs placebo; HR 0.74). 1

Offer enzalutamide 160 mg daily (improved OS, PSA response, and quality of life in post-docetaxel setting). 1

Offer cabazitaxel 25 mg/m² every 3 weeks for patients who progressed on docetaxel (approved for post-docetaxel mCRPC). 5

Consider docetaxel rechallenge if patient was benefiting at time of discontinuation due to reversible side effects, with drug holidays averaging 4-5 months between cycles. 1

PSMA-Targeted Radioligand Therapy

For patients with PSMA-positive disease (confirmed on Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat PET imaging) who have progressed after at least one androgen receptor pathway inhibitor AND at least one taxane regimen, offer 177Lu-PSMA-617. 6 This provides dramatic survival benefit (HR 0.62 for overall survival). 5

Exclude patients with PSMA non-expressing lesions (indicates poor response potential). 6

Monitoring requirements: 6

• PSA levels every 3-4 weeks initially
• Blood counts, renal and hepatic function before each cycle
• CT scans and bone scintigraphy for response assessment

Biomarker-Directed Therapy

For patients with HRR gene mutations (BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, CDK12), offer olaparib after progression on enzalutamide or abiraterone (HR 0.69 for overall survival in BRCA1/2 or ATM alterations). 5

For MSI-H/dMMR tumors, consider pembrolizumab in later lines of therapy. 1 Refer patients with MSI-H/dMMR for genetic counseling to assess for Lynch syndrome. 1

Treatment Sequencing Principles

Prioritize least toxic agents first in asymptomatic disease (novel hormonal agents before chemotherapy), but consider convenience of administration and patient preferences. 1 Sequential use of multiple agents is reasonable for patients who remain candidates for further therapy, with potential for 5+ years survival with modern sequential therapy. 2

Time to development of CRPC is the strongest predictor of response to second-line ARDT: shorter time to CRPC development predicts worse PSA-PFS and overall survival with subsequent ARDT. 3

Critical Pitfalls to Avoid

Never discontinue ADT even when adding novel therapies—maintaining castrate testosterone levels is essential for optimal outcomes. 2

Do not offer sipuleucel-T to symptomatic patients requiring narcotic pain medications—it is only indicated for asymptomatic or minimally symptomatic disease. 1, 2

Avoid estramustine due to increased toxicity without survival benefit. 1, 2

Do not use mitoxantrone over docetaxel in symptomatic patients with good performance status—docetaxel provides superior survival. 1

Recognize that antiandrogen withdrawal has no proven survival benefit despite observational data suggesting potential responses. 1

Be aware that 26% of patients on docetaxel experience serious adverse events and 11% discontinue due to toxicity—thorough risk-benefit discussion is warranted. 1