What are the latest promising treatments for metastatic castration-resistant prostate cancer (mCRPC) based on recent phase 3 trials?

Latest Promising Phase 3 Trials for mCRPC

The most recent and impactful phase 3 trials in mCRPC have established lutetium-177 PSMA-617 (VISION trial) and olaparib (PROfound trial) as breakthrough therapies, with PSMA-targeted radioligand therapy showing the most dramatic survival benefit in heavily pretreated patients. 1

PSMA-Targeted Radioligand Therapy

Lutetium-177 PSMA-617 combined with standard of care demonstrated the strongest recent phase 3 results, improving both radiographic progression-free survival (HR 0.40,99.2% CI 0.29-0.57, P < 0.001; medians: 8.7 vs 3.4 months) and overall survival (HR 0.62,95% CI 0.52-0.74, P < 0.001; medians: 15.3 vs 11.3 months) in the VISION trial. 1 This applies specifically to men with mCRPC who have received at least one taxane and at least one androgen receptor axis inhibitor. 1

PARP Inhibitor Therapy for DNA Repair Defects

Olaparib showed significant survival benefit in the updated PROfound trial analysis (HR 0.69,95% CI 0.50-0.97, P = 0.0175; medians: 19.1 vs 14.7 months) in men with BRCA1, BRCA2, or ATM alterations whose disease progressed on prior androgen receptor axis inhibitors. 1 The benefit was predominantly observed in men with BRCA alterations specifically, not uniformly across all DNA repair gene mutations. 1

Genomic Testing Requirements

• Perform next-generation sequencing on tumor samples to assess mutational status of at least BRCA1/2 in countries where PARP inhibitors are accessible for prostate cancer. 1
• Testing should be prioritized given that 20-30% of mCRPC patients present aberrations in DNA repair genes. 1
• While other DNA repair genes (PALB2, RAD50, RAD51, BRIP1) show promise, data remain sparse due to low frequency. 1

Non-Metastatic CRPC: Recent Breakthroughs

For non-metastatic CRPC at high risk for developing metastatic disease, apalutamide and enzalutamide with continued androgen deprivation represent the most recent phase 3 successes. 1

Apalutamide (SPARTAN Trial)

• Median metastasis-free survival was 40.5 months vs 16.2 months with placebo (HR=0.28; 95% CI, 0.23 to 0.35; P<0.001), representing a 72% reduction in risk of distant metastasis or death. 1
• Time to symptomatic progression (HR=0.45; P<0.001) and time to metastasis (HR=0.27; P<0.001) were significantly improved. 1
• This applies to patients with PSA doubling time ≤10 months on continued ADT. 1

Common Adverse Events to Monitor

• Fatigue (30.4% vs 21.1% placebo), hypertension (24.8% vs 19.8%), rash (23.8% vs 5.5%), and diarrhea (20.3% vs 15.1%) are the most frequent side effects. 2
• Seizure risk is low (0.2%) but requires patient counseling. 2

Established Post-Docetaxel Options

While not the newest trials, the following remain critical treatment options with proven phase 3 survival benefits:

Cabazitaxel

• FDA-approved for mCRPC patients who have progressed after docetaxel-based chemotherapy, representing standard of care in this setting with proven overall survival benefit. 3
• Works independently of PSMA expression and is effective against both bone and visceral metastases. 3
• Demonstrated 30% reduction in rate of death compared with mitoxantrone/prednisone in the TROPIC trial. 4

Enzalutamide and Abiraterone

• Both agents significantly prolong overall survival before and after docetaxel therapy in separate phase 3 trials. 5
• Enzalutamide showed OS improvement of 18.4 vs 13.6 months (HR 0.63, P < 0.001) in post-chemotherapy patients. 1
• Cross-resistance between these agents is a clinical concern when sequencing therapy. 3

Radium-223

• Approved for symptomatic patients with bone-limited disease only, showing both skeletal-related event reduction and overall survival benefit. 5
• Should be considered in third-line therapy for appropriate patients without visceral metastases. 5

Treatment Sequencing Algorithm

For newly diagnosed mCRPC:

1. If BRCA1/2 mutation positive and prior AR inhibitor failure → olaparib 1
2. If heavily pretreated (≥1 taxane + ≥1 AR inhibitor) with PSMA-positive disease → lutetium-177 PSMA-617 1
3. If post-docetaxel progression → cabazitaxel 3, 6
4. If non-metastatic with high-risk features (PSA doubling time ≤10 months) → apalutamide or enzalutamide 1

Critical caveat: PSA should not be the sole endpoint for treatment decisions; clinical and radiographic progression are more meaningful than PSA changes alone. 3