What is the next best course of action for a 62-year-old male with advanced prostate cancer and rising PSA 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 from 0.11 to 0.48 while on Xtandi (enzalutamide) and Orgovyx (relugolix), the next best step is to obtain imaging studies to assess for metastatic disease progression before changing therapy.

Assessment of PSA Progression

The patient demonstrates biochemical progression with:

• PSA increase from 0.11 (2/4/2025) to 0.48 (6/30/2025)
• Approximately 4-month interval between measurements
• Currently on dual therapy with Xtandi and Orgovyx

This represents a significant PSA rise while on effective androgen deprivation therapy (ADT), suggesting development of castration resistance.

Evaluation Steps

1. Confirm Testosterone Suppression

   • Verify castrate levels of testosterone (<50 ng/dL)
   • Ensure Orgovyx is effectively maintaining castration 1
   • Rule out medication non-adherence

2. Imaging Workup

   • Obtain bone scan to evaluate for bone metastases
   • Consider CT scan of chest/abdomen/pelvis to assess for soft tissue disease
   • Consider newer imaging modalities (PSMA PET/CT) if available for more sensitive detection of metastatic disease 2

3. PSA Kinetics Assessment

   • Calculate PSA doubling time (PSADT)
   • PSA velocity (0.37 ng/mL over ~5 months)
   • These parameters help stratify risk of metastatic progression 2

Treatment Decision Algorithm

If No Metastatic Disease Detected:

1. Continue Current Therapy with Close Monitoring

   • Monitor PSA every 1-2 months
   • Re-image if PSA continues to rise significantly
   • Consider clinical trial enrollment if available

2. Consider Treatment Intensification

   • Add docetaxel chemotherapy if rapid PSA doubling time (<6 months) 2
   • Consider additional hormonal manipulation (steroids, alternative antiandrogens) 2

If Metastatic Disease Detected:

1. Asymptomatic Metastases

   • Consider adding cabazitaxel chemotherapy 3
   • Consider radium-223 if bone-predominant disease 2
   • Evaluate for clinical trial eligibility

2. Symptomatic Metastases

   • Initiate chemotherapy with cabazitaxel 3
   • Consider palliative radiation for symptomatic bone lesions
   • Optimize pain management

Rationale for Recommendation

The ESMO guidelines recommend imaging studies when PSA rises on ADT to determine if there is radiographic evidence of disease progression before changing therapy 2. This approach is critical because:

1. The patient has already received multiple lines of therapy (taxotere, Orgovyx, Xtandi, radiation)
2. Treatment decisions differ significantly based on presence/absence of metastases
3. PSA progression alone may not always correlate with radiographic progression

Important Considerations

• Drug Interactions: Relugolix (Orgovyx) has been shown to maintain efficacy when used concomitantly with enzalutamide (Xtandi) 4

• Bone Health: Ensure the patient is on appropriate bone-protective agents given his history of advanced disease and ADT use 2

• PSA Interpretation: PSA results should be interpreted with caution as noted in the Orgovyx FDA label, which states "PSA results should be interpreted with caution because of the heterogeneity of the patient population studied" 1

• Quality of Life: Any treatment changes should prioritize maintaining quality of life while attempting to control disease progression 2

This approach ensures that treatment decisions are based on objective evidence of disease progression rather than PSA changes alone, which aligns with current guidelines for management of advanced prostate cancer.