Why is it necessary to continue androgen deprivation therapy (ADT) and apalutamide while undergoing Lutetium-177 (LU-177) infusions for metastatic castration-resistant prostate cancer?

Continuing ADT and Apalutamide During LU-177 Therapy for Metastatic Castration-Resistant Prostate Cancer

You must continue androgen deprivation therapy (ADT) and apalutamide during Lutetium-177 (LU-177) infusions for metastatic castration-resistant prostate cancer (mCRPC) to maximize survival benefits through complementary mechanisms of action targeting different aspects of tumor growth and progression. 1

Rationale for Continuing ADT

ADT remains the backbone therapy for all stages of advanced prostate cancer, including during other treatments. The NCCN Guidelines explicitly state that:

• The androgen receptor remains active in patients whose prostate cancer has recurred during ADT (castration-recurrent prostate cancer); thus, ADT should be continued 2
• In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies 2

Continuing ADT maintains castrate levels of testosterone, which is essential even when cancer becomes castration-resistant. This is because:

1. Not all cancer cells become fully castration-resistant at the same time
2. Even "resistant" cells may still be partially dependent on androgen signaling
3. Withdrawal of ADT could lead to testosterone recovery and accelerated disease progression

Role of Apalutamide During LU-177 Therapy

Apalutamide is an androgen receptor inhibitor that:

• Binds directly to the ligand-binding domain of the AR
• Inhibits AR nuclear translocation, DNA binding, and AR-mediated transcription 3
• Works synergistically with ADT to provide more complete androgen blockade

The TITAN trial demonstrated that apalutamide plus ADT:

• Significantly reduced the risk of death by 35% compared to ADT alone
• Maintained health-related quality of life
• Had a consistent safety profile in patients with metastatic castration-sensitive prostate cancer 4

Even after patients progress to castration-resistant disease, continuing apalutamide provides ongoing benefit by:

• Targeting persistent androgen receptor signaling through alternative pathways
• Preventing the emergence of additional resistance mechanisms
• Maintaining suppression of PSA, which correlates with improved outcomes 5

Synergistic Effects of Combination Therapy

Recent evidence suggests that combining LU-177 PSMA-617 with androgen receptor pathway inhibitors like apalutamide:

• Significantly prolongs progression-free survival compared to LU-177 PSMA-617 alone (11 vs. 5.6 months; HR, 0.47; 95% CI, 0.28-0.79; p < 0.01) 6
• Shows a trend toward improved overall survival (20.3 vs. 15.9 months; HR, 0.58; 95% CI, 0.33-1.02; p = 0.06) 6

This combination approach targets both hormone-dependent and hormone-independent cancer cells, maximizing treatment efficacy through complementary mechanisms:

1. ADT + apalutamide: Targets androgen-dependent pathways
2. LU-177: Delivers targeted radiation to PSMA-expressing tumor cells regardless of androgen sensitivity

Monitoring During Combination Therapy

While continuing ADT and apalutamide during LU-177 therapy:

• Monitor PSA levels regularly to assess treatment response
• Maintain testosterone at castrate levels (<50 ng/mL)
• Watch for potential side effects specific to the combination therapy, including:
  • Rash (more common with apalutamide, 23.8% vs. 5.5% with placebo)
  • Fatigue
  • Hypertension
  • Falls
  • Thyroid function changes (hypothyroidism occurred in 8.1% with apalutamide vs. 2.0% with placebo) 1

Conclusion

Discontinuing ADT and apalutamide during LU-177 therapy would likely compromise treatment outcomes and survival benefits. The current standard of care strongly supports continuing these therapies concurrently to achieve optimal disease control through complementary mechanisms of action.