First-Line Hormonal Treatment for Prostate Cancer
For metastatic hormone-sensitive prostate cancer in men aged 60 or older, first-line hormonal treatment should be androgen deprivation therapy (ADT) achieved through either bilateral orchiectomy or LHRH agonist/antagonist (chemical castration) alone, without the routine addition of antiandrogens. 1
Standard ADT Options
The following are equivalent first-line options for achieving castration 1:
- Bilateral orchiectomy (surgical castration) 1
- LHRH agonists (e.g., leuprolide, goserelin, triptorelin) administered as depot injections 1, 2
- LHRH antagonists (e.g., degarelix, relugolix) which offer equivalent testosterone suppression without requiring antiandrogen co-administration to prevent flare 1, 3
Key Distinction: LHRH Agonists vs. Antagonists
When using LHRH agonists, short-course antiandrogen therapy must be administered to prevent disease flare caused by the initial testosterone surge 1. This flare prevention is typically achieved with flutamide or bicalutamide for the first 2-4 weeks 4.
LHRH antagonists do not require antiandrogen co-administration because they directly block GnRH receptors without causing testosterone surge, achieving faster testosterone suppression 1, 3.
Combined Androgen Blockade: Not Recommended
The routine addition of antiandrogens (combined androgen blockade) to castration therapy is NOT recommended as first-line treatment 1. Here's why:
- Meta-analysis of 27 trials showed minimal survival benefit: 5-year survival of 25.4% with combined blockade vs. 23.6% with castration alone (P=0.11) 1
- While non-steroidal antiandrogens showed a small survival advantage (27.6% vs. 24.7%, P=0.005), this benefit is considered insufficient given the added toxicity and cost 1
- A large trial comparing orchiectomy alone vs. orchiectomy plus flutamide showed no survival benefit but demonstrated inferior quality of life with combined therapy 1
Enhanced First-Line Regimens for Metastatic Disease
For patients with metastatic hormone-sensitive prostate cancer who are fit for chemotherapy, triplet therapy (ADT + docetaxel + novel androgen receptor inhibitor) is now the preferred first-line approach 1, 5:
- ADT + docetaxel + darolutamide: 4-year overall survival of 62.7% vs. 50.4% with placebo (HR 0.68, P<0.001), representing a 23-month survival gain 5
- ADT + docetaxel + abiraterone: Median overall survival improved from 36.5 to 53.3 months (HR 0.66,95% CI 0.56-0.78) 6
This represents a paradigm shift from ADT monotherapy, particularly for high-volume disease (≥4 bone metastases with spread outside pelvis/vertebral column) 5.
Clinical Implementation Algorithm
For Metastatic Hormone-Sensitive Disease:
For Non-Metastatic Disease:
ADT is NOT routinely recommended for biochemical relapse unless 1:
- Symptomatic local disease progression, OR
- Proven metastases, OR
- PSA doubling time <3 months 1
Important Monitoring Requirements
When initiating ADT, establish baseline and periodic monitoring 5:
- Testosterone levels: Confirm castrate levels (<50 ng/dL or <1.7 nmol/L) 5
- PSA: Every 3-6 months 5
- Cardiovascular risk factors: Blood pressure monitoring for hypertension 5
- Bone health: Consider bone densitometry and bone-protective agents (denosumab or zoledronic acid) for patients with bone metastases 1, 5
- Metabolic monitoring: Assess for metabolic syndrome, diabetes risk 1
Common Pitfalls to Avoid
Do not add antiandrogens routinely to castration therapy beyond the initial flare prevention period with LHRH agonists 1
Do not use antiandrogen monotherapy (e.g., flutamide alone) as first-line treatment—it is inferior to castration 1
Do not delay ADT in symptomatic metastatic disease while pursuing additional testing 1
Do not discontinue ADT when adding second-line agents for castration-resistant disease—maintain castrate testosterone levels 1, 10
Do not overlook cardiovascular optimization before starting ADT, particularly in patients with pre-existing cardiac disease 10, 7