What are natural ways to decrease androgen levels in metastatic castration-resistant prostate cancer (mCRPC)?

Natural Ways to Decrease Androgen in mCRPC

There are no natural or non-pharmacological methods to decrease androgen levels in metastatic castration-resistant prostate cancer (mCRPC) that have demonstrated survival benefit or are recommended by clinical guidelines. In fact, the fundamental principle in mCRPC management is that androgen deprivation therapy (ADT) must be continued indefinitely to maintain castrate testosterone levels, and all effective treatments are pharmacological agents that either further suppress androgen production or block androgen receptor signaling 1, 2.

Why "Natural" Approaches Are Not Applicable in mCRPC

The Biology of mCRPC Contradicts Natural Androgen Reduction

• Despite castrate levels of androgens achieved through ADT, the androgen receptor remains active and continues to drive prostate cancer progression in mCRPC through intratumoral androgen synthesis and adrenal androgen production 1.
• The disease is termed "castration-resistant" precisely because standard castration (whether surgical or medical) has already failed to control the cancer, yet androgen signaling persists 3, 4.
• Prostate cancer cells in mCRPC adapt by upregulating enzymes involved in androgen synthesis, overexpressing androgen receptors, or developing mutant receptors with promiscuous ligand recognition 4.

Mandatory Continuation of Pharmacological ADT

• ADT with an LHRH agonist or antagonist must be continued indefinitely in all patients with mCRPC to maintain castrate serum testosterone levels (<50 ng/dL or <1.7 nmol/L), regardless of what additional therapies are added 2, 5.
• All FDA-approved therapies for mCRPC—including abiraterone, enzalutamide, apalutamide, docetaxel, cabazitaxel, sipuleucel-T, and radium-223—were studied and approved with concurrent ADT as the backbone therapy 1, 2.
• Discontinuing ADT in mCRPC is a critical clinical pitfall that must be avoided, as maintaining castrate testosterone levels remains essential throughout all subsequent treatments 2, 5.

Evidence-Based Pharmacological Androgen Reduction in mCRPC

Primary Androgen-Targeting Agents

• Abiraterone acetate (1,000 mg daily) plus prednisone (5 mg twice daily) is a CYP17 inhibitor that blocks androgen biosynthesis in the testes, adrenals, and prostate tumor tissue, improving overall survival by 4.6 months (HR 0.74) in post-docetaxel mCRPC and by 4.4 months (HR 0.81) in pre-chemotherapy mCRPC 1, 6.
• Enzalutamide is an androgen receptor antagonist that provides an overall survival gain of 4.8 months (HR 0.53-0.75) after docetaxel therapy 1, 7.
• Apalutamide and darolutamide are additional androgen receptor pathway inhibitors approved for specific mCRPC settings 1.

Critical Monitoring Requirements

• Serum testosterone must be verified to be <50 ng/dL (<1.7 nmol/L) through laboratory testing before diagnosing CRPC, and ADT delivery should be optimized or LHRH agents switched if testosterone is not adequately suppressed 2.
• Recent data suggest that a more stringent testosterone cutoff of <0.7 nmol/L (approximately 20 ng/dL) may be associated with improved patient outcomes, though most clinical trials have used the historical 1.7 nmol/L cutoff 8, 3.
• Testosterone levels should be monitored periodically throughout treatment to ensure maintenance of castrate levels 2.

Common Pitfalls to Avoid

• Never discontinue ADT when transitioning to secondary hormone therapies, chemotherapy, immunotherapy, or radiopharmaceuticals—these agents are added on top of continued ADT, not as replacements 2, 7, 5.
• Do not confuse "castration-resistant" with "androgen-independent"—mCRPC remains dependent on residual androgen signaling from non-gonadal sources 2, 8.
• Insufficient suppression of testosterone following ADT may have an adverse impact on survival, so verify castrate levels are achieved 3.

Treatment Algorithm for Androgen Reduction in mCRPC

1. Verify castrate testosterone levels (<50 ng/dL) and optimize ADT if needed 2
2. Continue ADT indefinitely with LHRH agonist/antagonist 2, 5
3. Add secondary androgen-targeting therapy (abiraterone + prednisone, enzalutamide, or apalutamide) based on prior treatments and patient factors 1
4. Sequence additional therapies (chemotherapy, immunotherapy, radiopharmaceuticals) while maintaining ADT backbone 2, 7
5. Monitor testosterone periodically to ensure castrate levels are maintained throughout all treatment phases 2