Management of Rising PSA on Relugolix and Enzalutamide
This patient has developed castration-resistant prostate cancer (CRPC) and requires immediate assessment of metastatic status followed by treatment intensification or switching to an alternative systemic therapy.
Confirm Castration-Resistant Status
First, verify this is true CRPC by documenting:
- Castrate testosterone levels (<50 ng/dL) while on relugolix 1
- Rising PSA defined as: PSA >2 ng/mL above nadir, at least 25% increase over nadir, confirmed by second PSA at least 3 weeks later 1
- Important caveat: In enzalutamide-treated patients with non-metastatic CRPC, even small PSA rises (median 1.4 ng/mL from nadir) can precede radiographic progression, so any PSA increase warrants closer monitoring rather than waiting for traditional PCWG2 criteria 2
Assess for Metastatic Disease
Obtain imaging immediately to determine disease state:
- Bone scan and CT abdomen/pelvis to evaluate for metastases 1, 3
- Consider PSMA-PET/CT if available for higher sensitivity in detecting metastases 4
- This distinction between metastatic and non-metastatic CRPC is critical as it determines subsequent treatment options 1
Treatment Options Based on Metastatic Status
If Non-Metastatic CRPC (M0 CRPC):
Switch to apalutamide or darolutamide as alternatives to enzalutamide 1:
- Apalutamide 240 mg daily demonstrated metastasis-free survival of 40.5 months versus 16.2 months with placebo (HR 0.28), with overall survival benefit of 73.9 versus 59.9 months 1
- Darolutamide 600 mg twice daily showed metastasis-free survival gain of 22.0 months (HR 0.41) with potentially better tolerability profile 1
- Continue relugolix concurrently to maintain castrate testosterone levels 5, 6
If Metastatic CRPC (M1 CRPC):
Add or switch to combination therapy 1:
- Abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily can be added to relugolix, as combination therapy is safe and effective 1, 6
- Docetaxel chemotherapy 75 mg/m² every 3 weeks if symptomatic or rapidly progressive disease 1
- Radium-223 if bone-predominant metastases without visceral disease 1, 3
- 177Lu-PSMA-617 if PSMA-positive disease after prior androgen receptor pathway inhibition and taxane therapy, showing 4-month overall survival benefit (HR 0.62) 1
Critical Monitoring Considerations
Any PSA rise in enzalutamide-treated patients requires heightened surveillance:
- In the PROSPER trial, radiographic progression often occurred without meeting traditional PCWG2 PSA progression criteria 2
- Median PSA increase at radiographic progression was only 1.4 ng/mL in enzalutamide-treated men versus 25.6 ng/mL in placebo 2
- Repeat imaging every 8-12 weeks if PSA continues rising, regardless of absolute PSA value 2
Relugolix Continuation
Continue relugolix throughout treatment changes 5, 6, 7:
- Relugolix maintains castrate testosterone levels when combined with abiraterone, apalutamide, or enzalutamide 6, 7
- Safety profile of relugolix combinations is consistent with individual drugs 6, 7
- Relugolix offers cardiovascular safety advantages over LHRH agonists, particularly important in this population 8
Common Pitfalls to Avoid
- Don't wait for traditional PSA progression criteria (25% rise, >2 ng/mL above nadir) in enzalutamide-treated patients—any confirmed rise warrants closer monitoring and imaging 2
- Don't assume adequate testosterone suppression—verify castrate levels, as up to 10% of patients on LHRH agonists fail to achieve castration, though this is less common with GnRH antagonists like relugolix 9
- Don't continue enzalutamide monotherapy once CRPC is confirmed—treatment intensification or switching is required 1
- Don't delay imaging—radiographic progression determines treatment strategy and may occur before significant PSA rises in enzalutamide-treated patients 2