What treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC) who have developed resistance to Zytiga (abiraterone acetate), specifically considering Nubeqa (darolutamide)?

Treatment Options for mCRPC After Zytiga (Abiraterone) Resistance

Nubeqa (Darolutamide) Is NOT Recommended After Abiraterone Failure

Nubeqa (darolutamide) should not be used for patients with mCRPC who have developed resistance to Zytiga (abiraterone) due to well-documented cross-resistance between all novel androgen receptor-targeted therapies. 1, 2, 3

Why Darolutamide Fails After Abiraterone

• Cross-resistance exists between all next-generation antiandrogen drugs (enzalutamide, abiraterone, apalutamide, and darolutamide) through the AKR1C3/AR-V7 axis in advanced prostate cancer. 3

• Abiraterone-resistant prostate cancer cells demonstrate cross-resistance to darolutamide through activation of the steroid hormone biosynthesis pathway and increased AKR1C3 expression. 3

• Sequential use of novel hormone therapies provides minimal benefit and is no longer a preferred strategy due to demonstrated cross-resistance mechanisms. 1, 2

• Darolutamide is FDA-approved only for non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel—not for post-abiraterone mCRPC. 4

Recommended Treatment Options After Abiraterone Failure

If Patient Has Already Received Docetaxel

Cabazitaxel 25 mg/m² every 3 weeks with prednisone/prednisolone 10 mg daily plus primary prophylactic G-CSF is the definitive preferred next-line therapy. 1, 2, 5

• The CARD trial provides Level 1 evidence demonstrating cabazitaxel superiority over switching between novel hormone therapies (radiographic PFS: 8.0 vs 3.7 months; HR 0.54, p<0.0001; OS: 13.6 vs 11.0 months; HR 0.64, p=0.008). 1, 5

• Cabazitaxel remains effective even after taxane exposure due to its low affinity to p-glycoprotein. 2, 6

If Patient Has NOT Received Docetaxel

Docetaxel-based chemotherapy is the standard recommendation, particularly for symptomatic disease or visceral metastases. 1, 2

• Docetaxel should not be delayed in symptomatic patients with good performance status (ECOG 0-1) as these patients derive the most benefit. 1

• Cabazitaxel can be considered for patients who progressed on abiraterone without prior docetaxel, though typically reserved for post-docetaxel settings. 1

PSMA-Directed Therapy

Lutetium-177 PSMA-617 is strongly recommended for patients with PSMA-positive disease confirmed by imaging who have failed both docetaxel and androgen pathway inhibitors. 1, 2

• The TheraP trial demonstrated superior PSA response rates with Lu-177-PSMA-617 (66%) compared to cabazitaxel (37%), with fewer grade 3-4 adverse events (33% vs 53%). 1

Bone-Directed Therapy

Radium-223 is a category 1 option specifically for patients with good performance status, symptomatic bone-predominant disease, and no visceral metastases. 7, 1, 2

• Radium-223 improves overall survival while specifically targeting bone metastases. 1, 2

• Do not use radium-223 in patients with visceral metastases—it is contraindicated and ineffective in this setting. 1, 5

Treatment Algorithm by Performance Status

Good Performance Status (ECOG 0-1)

1. Post-docetaxel + post-abiraterone: Cabazitaxel (preferred) 1, 2
2. No prior docetaxel: Docetaxel chemotherapy 1, 2
3. PSMA-positive disease post-docetaxel: Lu-177-PSMA-617 1, 2
4. Symptomatic bone disease without visceral metastases: Radium-223 1, 2

Poor Performance Status (ECOG 2+)

• Palliative care is the primary recommendation for patients with poor performance status who progressed on abiraterone after docetaxel. 1, 2

• Selected patients may receive ketoconazole plus steroid or radionuclide therapy as palliative options. 1, 2

Critical Pitfalls to Avoid

• Do not switch from abiraterone to enzalutamide (or add darolutamide) expecting meaningful benefit—the CARD trial definitively showed cabazitaxel superiority over this approach. 1, 2

• Do not continue sequential novel hormone therapy—cross-resistance mechanisms make this strategy ineffective. 1, 2, 3

• Do not delay chemotherapy in symptomatic patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 1

• Clinical trials should be actively considered throughout the treatment course for patients with limited standard options. 1, 5