What are the next steps for a patient with progressive prostate cancer and retroperitoneal and bone metastasis on Bicalutamide (Casodex) since a specified date?

Management of Progressive Metastatic Castration-Resistant Prostate Cancer on Bicalutamide

Immediately discontinue bicalutamide and switch to enzalutamide or abiraterone plus prednisone as first-line therapy for castration-resistant prostate cancer (CRPC), while continuing LHRH agonist/antagonist therapy and initiating mandatory bone-protective therapy with denosumab or zoledronic acid. 1, 2, 3

Immediate Treatment Escalation Required

Your patient has developed castration-resistant disease, defined by progression despite androgen deprivation therapy. Bicalutamide monotherapy is insufficient for metastatic CRPC and must be replaced with more potent androgen receptor pathway inhibitors. 1, 4

First-Line Systemic Therapy for Metastatic CRPC

Preferred option: Enzalutamide 160 mg orally once daily 1, 3

• Enzalutamide demonstrates superior efficacy compared to bicalutamide, with median time to progression of 15.7 months versus 5.8 months for bicalutamide (HR 0.44), representing a 76% reduction in risk of progression or death (HR 0.24). 1, 3
• This is a category 1, preferred treatment recommendation from NCCN for patients with metastatic CRPC without prior novel hormone therapy. 1, 3
• Enzalutamide has no significant cardiovascular concerns compared to placebo, with major adverse cardiovascular events occurring in only 5% versus 3% on placebo. 1, 3
• Common side effects include fatigue (33-34%), diarrhea (21%), hot flushes (20%), hypertension (12%), and headache (12%), with seizure risk remaining low at 0.6-0.9%. 1, 3

Alternative option: Abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily 1

• Abiraterone is a category 1 recommendation for post-docetaxel CRPC and category 2A for pre-chemotherapy asymptomatic/minimally symptomatic CRPC. 1
• Must be taken in fasting state and requires glucocorticoid co-administration to prevent mineralocorticoid excess (hypertension, hypokalemia, peripheral edema). 1
• Monitor serum electrolytes closely during therapy. 1

Critical Decision Point: Symptomatic vs Asymptomatic Disease

For asymptomatic or minimally symptomatic patients: Enzalutamide or abiraterone are preferred first-line options. 1, 2

For symptomatic patients with significant disease burden: Consider docetaxel 75 mg/m² every 3 weeks as first-line therapy, which has demonstrated survival benefit in two phase III trials (median survival 17-19.2 months versus 15-16.3 months with mitoxantrone). 1, 2

Mandatory Bone-Protective Therapy

All patients with bone metastases must receive bone-protective agents immediately. 2, 5

• Preferred: Denosumab 120 mg subcutaneously every 4 weeks - superior to zoledronic acid in delaying skeletal-related events (HR 0.82, P=0.0002). 2, 5
• Alternative: Zoledronic acid 4 mg intravenously every 3-4 weeks - adjust dose for renal impairment (not recommended if creatinine clearance <30 mL/min). 1, 2
• Mandatory preventive measures: Dental screening before initiation to prevent osteonecrosis of the jaw, and ensure adequate calcium and vitamin D supplementation. 2, 5

Essential Monitoring and Supportive Care

Immediate Diagnostic Requirements

• Urgent spine MRI if any back pain or neurological symptoms to rule out spinal cord compression, which occurs in approximately 95% of patients with metastatic spinal cord compression. 5
• Restaging with CT and bone scan before initiating new therapy. 1
• Baseline PSA, testosterone level (confirm <50 ng/dL or <1.7 nmol/L), liver function tests, and complete blood count. 1

Ongoing Surveillance

• Monitor PSA and clinical examinations every 3 months. 1, 4
• Repeat imaging (CT, bone scan) every 3-6 months or when clinically indicated. 1
• Liver function tests regularly, especially in first 4 months if considering re-challenge with any antiandrogen. 4
• Bone densitometry monitoring for osteoporosis and screening for metabolic syndrome complications. 2, 5

Palliative Radiation for Symptomatic Bone Metastases

• Single 8 Gy fraction provides equivalent pain relief to multi-fraction regimens for painful bone metastases, with 50-58% achieving pain relief and 30-35% achieving complete resolution. 2, 5
• Reserve radiation for symptomatic sites or impending pathologic fractures. 2

Treatment Sequencing Upon Further Progression

If progression occurs on enzalutamide or abiraterone (first-line CRPC therapy): 1, 2

1. For patients without visceral metastases and prior enzalutamide/abiraterone:

   • Docetaxel 75 mg/m² every 3 weeks (category 1)
   • Radium-223 for symptomatic bone metastases (category 1)
   • Sipuleucel-T if not previously received
   • Pembrolizumab for MSI-high or dMMR tumors (category 2B)

2. For patients with prior docetaxel:

   • Cabazitaxel (category 1)
   • Alternative novel hormone therapy (abiraterone if received enzalutamide, or vice versa) (category 1)
   • Radium-223 for symptomatic bone metastases (category 1)
   • 177Lu-PSMA-617 for PSMA-expressing tumors

3. For patients with visceral metastases:

   • Biopsy should be considered to confirm adenocarcinoma histology
   • Docetaxel and enzalutamide are category 1 recommendations
   • Abiraterone/prednisone is an option

Critical Pitfalls to Avoid

• Do not continue bicalutamide monotherapy - it is inadequate for CRPC and delays effective treatment. 1, 3, 4
• Do not stop LHRH agonist/antagonist therapy - maintain castrate testosterone levels throughout all subsequent treatments. 1, 4
• Do not delay bone-protective therapy - initiate immediately with first CRPC treatment to prevent skeletal-related events. 1, 2
• Do not use PSA progression alone to determine treatment failure - require two of three criteria (PSA, radiographic, or clinical progression) before switching therapy. 1
• Antiandrogen withdrawal phenomenon: Consider a treatment-free period of antiandrogen while continuing LHRH analog if PSA rises, as some patients experience PSA decline after bicalutamide withdrawal. 4

Prognosis and Patient Counseling

• Median survival for metastatic CRPC is less than 2 years, with time to castration resistance averaging 14-30 months from ADT initiation. 2
• More than 90% of CRPC patients have bone metastases. 2
• Early referral to palliative care services is recommended for symptom management and quality of life optimization. 1
• Encourage participation in clinical trials, as novel therapies continue to emerge. 1