Is androgen deprivation therapy (ADT) still necessary in patients with metastatic castration-resistant prostate cancer (mCRPC) who have undergone orchiectomy?

Should ADT Be Continued After Orchiectomy in Metastatic Castration-Resistant Prostate Cancer?

No, patients who have undergone bilateral orchiectomy do not need additional ADT with LHRH agonists or antagonists, as surgical castration permanently maintains castrate testosterone levels. 1, 2

Rationale for This Recommendation

Surgical Castration is Equivalent to Medical Castration

• Bilateral orchiectomy and medical castration (LHRH agonists/antagonists) are considered therapeutically equivalent for achieving and maintaining castrate testosterone levels (<50 ng/dL) 1
• The FDA label for enzalutamide explicitly states that patients with CRPC or mCSPC receiving enzalutamide "should also receive a GnRH analog concurrently or should have had bilateral orchiectomy" 2
• This "or" designation confirms that orchiectomy is a complete alternative to ongoing medical ADT, not requiring supplementation 2

The Principle Behind Continuing ADT

The recommendation to "continue ADT" in CRPC specifically refers to maintaining castrate testosterone levels, not necessarily continuing LHRH therapy 1, 3. The biological rationale is:

• Castration-resistant disease remains androgen-dependent through residual androgen signaling from adrenal and intratumoral sources 3, 4, 5
• All novel therapies for mCRPC (abiraterone, enzalutamide, chemotherapy) were studied with maintained castrate testosterone as the backbone 3, 6
• The critical factor is maintaining testosterone <50 ng/dL (ideally <20 ng/dL), not the method of achieving it 7, 4

Orchiectomy Provides Permanent Castration

• Surgical castration reduces serum testosterone to <20 ng/dL in approximately 75% of patients, often achieving lower levels than medical castration 7
• Unlike LHRH agonists, orchiectomy has no risk of testosterone escape from late dosing or inadequate suppression 4
• The effect is immediate and permanent, eliminating concerns about treatment adherence or breakthrough testosterone 7

Clinical Implementation

What to Monitor

• Verify castrate testosterone levels (<50 ng/dL, ideally <20 ng/dL) at baseline after orchiectomy to confirm adequate suppression 1, 3, 4
• Periodic testosterone monitoring is still recommended to detect rare cases of incomplete orchiectomy or ectopic testosterone production 3, 4
• If testosterone rises above castrate levels post-orchiectomy, investigate for incomplete surgery or adrenal sources and consider adding medical ADT 4

Treatment Sequencing After Orchiectomy

All subsequent therapies should be added without additional LHRH therapy:

• Secondary hormone therapies (abiraterone + prednisone, enzalutamide, apalutamide) can be initiated directly 1, 3, 2
• Chemotherapy (docetaxel, cabazitaxel) proceeds without additional ADT 3, 8
• Immunotherapy (sipuleucel-T) and radiopharmaceuticals (radium-223, 177Lu-PSMA-617) are given without LHRH agents 3, 8
• Targeted therapies (PARP inhibitors, PSMA-directed therapy) require only maintained castrate levels, not ongoing LHRH 3, 8

Common Pitfalls to Avoid

Do Not Add Redundant LHRH Therapy

• Adding LHRH agonists/antagonists after orchiectomy provides no additional benefit and adds unnecessary cost, side effects, and treatment burden 1
• The guideline recommendation to "continue ADT" is often misinterpreted as requiring LHRH therapy even after surgical castration 3, 9

Verify Adequate Castration Was Achieved

• Rare cases of incomplete orchiectomy or retained testicular tissue can result in inadequate testosterone suppression 7
• If PSA progression occurs with testosterone >50 ng/dL post-orchiectomy, investigate the cause before assuming true castration resistance 4

Distinguish Between Castration Method and Castration State

• The critical therapeutic principle is maintaining castrate testosterone levels, not the specific method used 3, 4, 9
• Guidelines emphasizing "life-long ADT" refer to maintaining castrate state, which orchiectomy accomplishes permanently 1, 3

Special Considerations

When Medical ADT Might Still Be Added

The only scenario where adding LHRH therapy post-orchiectomy would be appropriate:

• Documented testosterone levels persistently >50 ng/dL despite confirmed bilateral orchiectomy, suggesting incomplete surgery or ectopic production 4
• In this rare situation, adding an LHRH agonist/antagonist may help achieve adequate suppression 4

Quality of Life Implications

• Patients who chose orchiectomy specifically to avoid ongoing injections should not be subjected to LHRH therapy unless testosterone is inadequately suppressed 1
• The side effect profile of castration (hot flashes, sexual dysfunction, metabolic changes) is identical whether achieved surgically or medically 1, 7