What is the next best step in management for a 62-year-old male with advanced stage prostate cancer and rising PSA levels on Xtandi (Enzalutamide) and Orgovyx (Relugolix)?

Management of Rising PSA in Advanced Prostate Cancer on Xtandi and Orgovyx

For a 62-year-old male with advanced prostate cancer showing PSA progression on Xtandi (enzalutamide) and Orgovyx (relugolix), the next best step is to switch to cabazitaxel chemotherapy while maintaining androgen deprivation therapy with Orgovyx.

Assessment of Current Status

The patient shows clear evidence of biochemical progression:

• PSA increased from 0.11 to 0.48 ng/mL over a 5-month period (February to June 2025)
• Testosterone levels remain suppressed (13-19 ng/dL), indicating effective androgen deprivation
• CEA levels have slightly decreased (6.7 to 5.7)

This pattern indicates development of castration-resistant prostate cancer (CRPC) despite treatment with both:

• Orgovyx (relugolix) - a GnRH receptor antagonist for testosterone suppression
• Xtandi (enzalutamide) - an androgen receptor inhibitor

Treatment Algorithm for CRPC with Rising PSA on Current Therapy

1. Confirm PSA progression

   • The patient's PSA has more than quadrupled over 5 months while on therapy
   • This meets criteria for biochemical progression in CRPC

2. Verify castration status

   • Testosterone levels remain well below castrate level (<50 ng/dL) 1
   • This confirms adequate androgen deprivation therapy

3. Next therapeutic options:

   a) Recommended: Cabazitaxel chemotherapy

   • Evidence shows significant activity of cabazitaxel in patients who have progressed on docetaxel and next-generation hormonal agents (enzalutamide/abiraterone) 2
   • In patients previously treated with docetaxel and enzalutamide, cabazitaxel demonstrated:
     • 39% PSA response rate (≥50% decline)
     • 14% radiologic response rate
     • Median progression-free survival of 4.6 months 2
   • Continue Orgovyx to maintain testosterone suppression 3

   b) Alternative options:

   • Abiraterone (if not previously used) 1
   • Radium-223 (if bone-predominant disease without visceral metastases) 1
   • Clinical trial participation

Rationale for Recommendation

1. Sequential therapy effectiveness:

   • ESMO guidelines recommend docetaxel for men with metastatic CRPC 1
   • Since this patient has already received taxotere (docetaxel), cabazitaxel is the appropriate next chemotherapy option 1
   • Research demonstrates cabazitaxel remains effective after progression on enzalutamide 2

2. Maintenance of ADT:

   • Guidelines recommend continuing ADT (Orgovyx) even during progression to maintain castrate testosterone levels 1
   • The HERO study demonstrated that relugolix (Orgovyx) can be safely used with other prostate cancer treatments including enzalutamide and docetaxel 3

3. Monitoring considerations:

   • Continue regular PSA monitoring to assess treatment response
   • Consider imaging studies to evaluate for metastatic progression
   • Monitor for treatment-related toxicities

Important Caveats and Considerations

• Maintain androgen deprivation: Even when changing other therapies, continuous ADT is recommended as first-line treatment of metastatic disease 1

• Imaging before treatment change: Consider restaging with bone scan and CT/MRI to assess for new metastases before initiating new therapy 1

• Potential side effects of cabazitaxel: Prepare for and monitor for neutropenia, fatigue, diarrhea, and neuropathy

• Alternative if chemotherapy contraindicated: If the patient is not a candidate for chemotherapy, consider radium-223 for bone-predominant disease or clinical trial enrollment 1

• Avoid discontinuation based solely on PSA: While PSA progression is concerning, treatment decisions should incorporate clinical status and imaging findings 4

By maintaining androgen deprivation with Orgovyx while adding cabazitaxel, this approach follows evidence-based guidelines for sequential therapy in advanced prostate cancer that has become resistant to current treatment.