Do you continue Androgen Deprivation Therapy (ADT) when taking Lutetium-177 (LU-177) for metastatic castration-resistant prostate cancer?

Continuing ADT During Lutetium-177 PSMA Therapy for Metastatic Castration-Resistant Prostate Cancer

Yes, androgen deprivation therapy (ADT) should absolutely be continued when taking Lutetium-177 (Lu-177) PSMA therapy for metastatic castration-resistant prostate cancer. This recommendation is strongly supported by clinical guidelines and research evidence.

Rationale for Continuing ADT with Lu-177 PSMA Therapy

Guideline Recommendations

• The ESMO consensus guidelines explicitly state that "patients with CRPC should continue with life-long ADT" with the highest strength of recommendation (A) 1
• NCCN guidelines emphasize that "the androgen receptor remains active in patients whose prostate cancer has recurred during ADT (castration-recurrent prostate cancer); thus, ADT should be continued" 1
• The AUA guideline reinforces this approach by recommending continued ADT for all patients with castration-resistant prostate cancer 1

Biological Basis

• Even in castration-resistant disease, the androgen receptor remains active and continues to drive tumor growth
• Maintaining castrate testosterone levels (<50 ng/mL) is essential to prevent stimulation of remaining androgen-sensitive cancer cells
• Discontinuing ADT could lead to a testosterone flare that may accelerate disease progression

Evidence Supporting Combined Approach

Recent research demonstrates the benefits of combining Lu-177 PSMA with ongoing ADT:

• A 2024 study showed that combining Lu-177 PSMA-617 with androgen receptor pathway inhibitors significantly prolonged progression-free survival compared to Lu-177 PSMA-617 alone (11 vs. 5.6 months; HR 0.47; p<0.01) 2
• The pivotal VISION trial, which led to FDA approval of Lu-177 PSMA-617, included patients who maintained ADT throughout treatment, demonstrating improved overall survival (15.3 vs. 11.3 months) 3

Treatment Algorithm for mCRPC Patients Receiving Lu-177 PSMA

1. Continue baseline ADT (LHRH agonist/antagonist or surgical castration)

   • Maintain castrate testosterone levels (<50 ng/mL)
   • Monitor testosterone levels periodically

2. Add Lu-177 PSMA-617 therapy

   • Typical regimen: 7.4 GBq every 6 weeks for 4-6 cycles 3
   • Monitor for side effects (particularly hematologic toxicity)

3. Consider additional hormonal manipulations if needed

   • Second-line hormonal therapies may include:
     • Androgen receptor inhibitors (enzalutamide)
     • CYP17 inhibitors (abiraterone with prednisone)
     • Other antiandrogens, ketoconazole, or steroids 1

Important Considerations

• Bone health monitoring: ADT increases risk of osteoporosis and fractures; consider calcium/vitamin D supplementation and bone-targeted agents when appropriate
• Metabolic monitoring: ADT increases risk of diabetes and cardiovascular disease; regular screening is recommended
• Quality of life: Manage ADT-related side effects (hot flashes, fatigue, sexual dysfunction) to maintain treatment adherence

Potential Pitfalls

1. Discontinuing ADT prematurely: This could lead to testosterone recovery and stimulation of hormone-sensitive cancer cells
2. Inadequate testosterone suppression: Ensure testosterone levels are consistently below castrate level (<50 ng/mL)
3. Overlooking ADT side effects: Proactively manage side effects to maintain quality of life and treatment adherence

In conclusion, ADT remains a cornerstone of treatment for metastatic castration-resistant prostate cancer, even when adding newer therapies like Lu-177 PSMA. The evidence strongly supports continuing ADT indefinitely in these patients to optimize outcomes and survival.