What current clinical trials are underway to treat castration-resistant metastatic prostate cancer?

Current Clinical Trials for Castration-Resistant Metastatic Prostate Cancer

There are numerous ongoing clinical trials evaluating novel therapeutic approaches for castration-resistant metastatic prostate cancer (mCRPC), with immunotherapy combinations and targeted therapies representing the most promising areas of investigation. 1, 2

Current Landscape of Clinical Trials

Immunotherapy-Based Trials

Immunotherapy trials are particularly active in mCRPC despite the historically "cold" immunologic nature of prostate cancer:

• Checkpoint inhibitor combinations:

  • PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors
  • Checkpoint inhibitors with standard therapies (chemotherapy, androgen receptor pathway inhibitors)
  • Only pembrolizumab is currently approved for mCRPC patients with MSI-H/dMMR tumors 3

• Novel immunotherapy approaches:

  • B7-H3 targeted therapies (emerging checkpoint target specific to prostate cancer) 3
  • Vaccine-based therapies to enhance immune recognition
  • CAR T-cell therapies targeting prostate-specific antigens
  • Bi-specific T-cell engagers (BiTEs) 2
  • Adenosine pathway inhibitors to overcome immunosuppression 2

Combination Therapy Trials

The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) has established standardized trial designs and endpoints for mCRPC studies, emphasizing the importance of:

• Radiographic progression-free survival (rPFS)
• Overall survival (OS)
• Symptomatic skeletal events (SSEs) as more clinically meaningful than skeletal-related events (SREs) 4

Key combination approaches being investigated include:

1. Immunotherapy + Targeted Therapy:

   • Checkpoint inhibitors with PARP inhibitors (especially in patients with DNA repair defects)
   • Checkpoint inhibitors with tyrosine kinase inhibitors 2

2. Immunotherapy + Standard Treatments:

   • Checkpoint inhibitors with novel hormonal therapies (abiraterone, enzalutamide)
   • Immunotherapy with chemotherapy (docetaxel, cabazitaxel)
   • Immunotherapy with radiopharmaceuticals (radium-223) 2, 5

3. Sequencing Trials:

   • Optimal sequencing after progression on docetaxel or abiraterone in the castration-sensitive setting 5
   • Trials evaluating cabazitaxel (25 mg/m²) with G-CSF prophylaxis versus abiraterone/enzalutamide in patients who progressed on prior therapy 6

Emerging Trial Designs

Recent trials are incorporating:

• Biomarker-driven selection: Enriching for patients with specific genomic alterations (DNA repair defects, MSI-H)

• Novel endpoints:

  • Time to symptomatic skeletal events (SSEs) rather than SREs 4
  • Proportion of patients progression-free at fixed timepoints (6 and 12 months) 4
  • No longer clinically benefiting (NLCB) concept rather than strict radiographic progression 4

• Standardized imaging assessment:

  • Using RECIST 1.1 with modifications for bone metastases
  • The "2+2 rule" for bone scan progression (at least two new lesions on first post-treatment scan, confirmed by at least two additional new lesions on next scan) 4
  • Separate reporting of progression by site (bone, nodes, viscera) 4

Practical Considerations for Patients

When considering clinical trials for mCRPC patients:

• Prioritize trials based on prior therapy exposure:

  • For patients progressing after docetaxel and abiraterone/enzalutamide, cabazitaxel-based combination trials show promise (CARD trial showed superiority of cabazitaxel over abiraterone/enzalutamide rechallenge) 6
  • For patients with bone-predominant disease, radium-223 combination trials may be appropriate 7

• Consider molecular profiling:

  • Trials targeting specific molecular alterations (PARP inhibitors for BRCA mutations)
  • Immunotherapy trials for MSI-H/dMMR patients

Common Pitfalls to Avoid

• Overlooking patient selection criteria: Many trials have specific requirements regarding prior therapies and progression patterns
• Ignoring pseudoprogression: Particularly important in immunotherapy trials where initial worsening may occur before improvement 4
• Failing to distinguish between types of progression: Trials now separate PSA progression from radiographic and symptomatic progression 4

The landscape of mCRPC clinical trials continues to evolve rapidly, with immunotherapy combinations and precision medicine approaches representing the most promising avenues for improving outcomes in this challenging disease.