What is the first-line hormonal treatment agent for a male patient in his 60s or older with prostate cancer?

First-Line Hormonal Treatment for Prostate Cancer in Men ≥60 Years

Bilateral orchiectomy or LHRH agonists (such as goserelin or leuprolide) are the recommended first-line hormonal treatments for men aged 60 or older with androgen-sensitive metastatic, recurrent, or progressive prostate cancer. 1

Standard First-Line Options

The evidence strongly supports two equivalent approaches for achieving castration:

• Bilateral orchiectomy (surgical castration) provides the most rapid testosterone suppression (within 12-24 hours) and achieves the lowest castrate testosterone levels, which may correlate with better disease control 2. However, it is irreversible and less commonly chosen due to psychological impact 3.

• LHRH agonists (leuprolide, goserelin, triptorelin) administered as depot injections are equally effective alternatives 1, 4. These agents require mandatory short-course antiandrogen coverage for 7 days to 3-4 weeks to prevent testosterone flare, which can cause disease progression or spinal cord compression in patients with extensive bone metastases 5, 3.

• LHRH antagonists (degarelix, relugolix) offer equivalent testosterone suppression without requiring antiandrogen co-administration, as they do not cause initial testosterone surge 6, 5.

What NOT to Do: Combined Androgen Blockade

Routine addition of antiandrogens to castration therapy (combined androgen blockade) is NOT recommended as first-line treatment. 1, 6, 5

The evidence is clear on this point:

• Meta-analysis of 27 trials showed minimal survival benefit: 5-year survival of 25.4% with combined blockade versus 23.6% with castration alone (P=0.11) 1
• The small potential survival benefit (approximately 2-3% at 5 years) does not justify the increased toxicity and cost 1, 6
• Steroidal antiandrogens should never be offered as monotherapy 1

Clinical Implementation Algorithm

For Metastatic Hormone-Sensitive Disease:

1. Assess fitness for chemotherapy and disease burden 6

2. If fit for chemotherapy: Consider triplet therapy (ADT + docetaxel + novel androgen receptor inhibitor such as darolutamide or abiraterone), which improves 4-year overall survival to 62.7% versus 50.4% with placebo (HR 0.68, P<0.001) 6

3. If not fit for chemotherapy or patient preference: Initiate standard ADT alone with either:

   • Bilateral orchiectomy 1, OR
   • LHRH agonist with 7-day to 4-week antiandrogen coverage 5, 3, OR
   • LHRH antagonist without antiandrogen coverage 6, 5

For Non-Metastatic Disease with Biochemical Recurrence:

• ADT is NOT routinely recommended unless the patient has symptomatic local disease progression, proven metastases, or PSA doubling time <3 months 1, 6

For Patients Requiring GnRH Analog:

• Patients with castration-resistant or metastatic castration-sensitive prostate cancer should receive a GnRH analog concurrently or have had bilateral orchiectomy 7
• Patients with non-metastatic castration-sensitive disease with biochemical recurrence at high risk for metastasis may be treated with or without a GnRH analog 7

Critical Monitoring Requirements

Once ADT is initiated, establish the following monitoring protocol:

• Testosterone levels: Confirm castrate levels (<50 ng/dL or <1.7 nmol/L) 6
• PSA monitoring: Every 3-6 months 6
• Cardiovascular risk assessment: Comprehensive evaluation before starting ADT, especially in patients >65 years with pre-existing cardiovascular conditions 5
• Bone health: Bone densitometry and consideration of bone-protective agents (denosumab or zoledronic acid) for patients with bone metastases 6
• Metabolic monitoring: Assess for diabetes, dyslipidemia, and weight gain 6

Important Clinical Caveats

Testosterone flare prevention is critical: Patients with extensive symptomatic bone metastases are at high risk for spinal cord compression during testosterone flare with LHRH agonists 3. This makes proper antiandrogen coverage absolutely essential when using LHRH agonists rather than antagonists.

Timing considerations: For metastatic or progressive disease, immediate versus deferred ADT results in 17% reduction in prostate cancer-specific mortality but 15% increase in non-prostate cancer mortality, with no overall survival advantage 1. However, the lower incidence of severe adverse events including cord compression with early ADT has established immediate initiation as standard practice 8.

Product administration: Advise patients to take enzalutamide (if used as part of combination therapy) whole with sufficient water, as severe dysphagia or choking related to product size can occur 7.