What is the treatment approach for bone metastases in metastatic castration-resistant prostate cancer (mCRPC)?

Treatment of Bone Metastases in Metastatic Castration-Resistant Prostate Cancer

For bone metastases in mCRPC, you must initiate bone-targeted therapy with denosumab 120 mg subcutaneously every 4 weeks (preferred) or zoledronic acid 4 mg intravenously every 3-4 weeks to prevent skeletal-related events, alongside systemic therapy tailored to symptom burden and prior treatments. 1

Bone-Targeted Therapy: The Foundation

Denosumab is superior to zoledronic acid and should be your first choice for preventing skeletal-related events (SREs) in mCRPC patients with bone metastases. 1

• Denosumab delays time to first SRE by a median of 3.6 months compared to zoledronic acid (20.7 vs 17.1 months; HR 0.82, P=0.008 for superiority). 1
• Neither agent improves overall survival, but both significantly reduce pathologic fractures, spinal cord compression, and need for bone radiation or surgery. 1
• Start bone-targeted therapy early in patients at high risk for SREs, defined by tumor burden (>3 bone metastases, elevated alkaline phosphatase), anatomic location of metastases, or prior history of SRE. 1

Practical Implementation of Bone-Targeted Agents

Before initiating denosumab or zoledronic acid:

• Correct pre-existing hypocalcemia and ensure adequate calcium (1000 mg daily) and vitamin D (at least 400 IU daily) supplementation. 1, 2
• Obtain baseline dental evaluation to assess osteonecrosis of the jaw (ONJ) risk; prophylactic antibiotics may be considered for high-risk dental procedures. 1
• For zoledronic acid specifically, check renal function and serum calcium before each dose; dose-reduce for creatinine clearance 30-60 mL/min and hold for <30 mL/min. 1
• For denosumab, measure serum calcium before each injection; it can be used in severe renal impairment but hypocalcemia risk increases substantially (13% vs 6% with zoledronic acid). 1, 2

Critical warning for advanced kidney disease patients (eGFR <30 mL/min): These patients face markedly increased risk of severe, life-threatening hypocalcemia with denosumab, particularly if chronic kidney disease-mineral bone disorder (CKD-MBD) is present. Evaluate for CKD-MBD with intact PTH, serum calcium, 25(OH) vitamin D, and 1,25(OH)2 vitamin D before treatment decisions, and ensure supervision by a provider with CKD-MBD expertise. 2

• Optimal duration of bone-targeted therapy remains unclear, but a trial showed zoledronic acid every 12 weeks was noninferior to every 4 weeks after initial treatment period. 1
• Monitor serum calcium regularly throughout treatment with either agent. 1

Systemic Therapy Selection Based on Clinical Context

For Asymptomatic or Mildly Symptomatic Chemotherapy-Naïve mCRPC

Offer abiraterone acetate plus prednisone OR enzalutamide as first-line systemic therapy. 1

• Both agents have Level I, Grade A evidence for improving progression-free survival and overall survival in this population. 1
• Choice between these agents should be based on patient comorbidities, side effect profiles, and drug interactions. 1
• Sipuleucel-T is an alternative option with Level II, Grade B evidence for asymptomatic/mildly symptomatic chemotherapy-naïve patients. 1

For Symptomatic Bone-Predominant Disease Without Visceral Metastases

Radium-223 dichloride is the preferred option as it provides both symptomatic relief and survival benefit. 1

• Radium-223 improved overall survival by 3.6 months and delayed symptomatic skeletal events by 5.8 months in the ALSYMPCA trial. 1
• Critical requirement: All patients receiving radium-223 must receive concomitant denosumab or zoledronic acid, based on ERA-223 trial findings showing increased fracture risk without bone-targeted therapy. 1
• Radium-223 is contraindicated in patients with visceral metastases. 1
• Common adverse events include myelosuppression and diarrhea. 1

For Symptomatic mCRPC or After Novel Hormone Therapy Failure

Docetaxel 75 mg/m² every 3 weeks is the standard chemotherapy option with Level I, Grade A evidence. 1, 3

• For patients progressing after docetaxel, cabazitaxel is superior to switching between abiraterone and enzalutamide due to cross-resistance between these novel hormone therapies. 1, 4
• The CARD trial demonstrated cabazitaxel significantly improved clinical outcomes over enzalutamide/abiraterone in post-docetaxel patients who had received the alternate hormone therapy. 1
• Enzalutamide or abiraterone can still be used post-docetaxel if not previously given, with Level I, Grade A evidence. 1

Radiation Therapy for Symptomatic Bone Lesions

A single 8 Gy fraction of external beam radiation is the preferred approach for palliation of painful bone metastases. 1, 3

• Single-fraction 8 Gy provides equivalent pain relief to multi-fraction regimens (e.g., 30 Gy in 10 fractions) but is more convenient and cost-effective. 3
• For patients with good performance status, limited disease, and single area of spinal cord compression, surgical decompression followed by radiation should be considered. 1
• Stereotactic body radiation therapy (SBRT) can improve local control and ambulation in select patients with spinal metastases post-operatively. 1

Alternative Radiopharmaceuticals

Strontium-89 or samarium-153 remain options for palliation of bone pain, though they are seldom used given availability of radium-223 and lack of survival benefit. 1

Critical Monitoring and Emergency Management

Spinal Cord Compression Surveillance

MRI of the spine is recommended to detect subclinical cord compression in all men with mCRPC and vertebral metastases. 1, 3

• Urgent MRI is very strongly recommended (Level III, Grade A) for any patient with vertebral metastases who develops neurological symptoms. 1, 3
• If cord compression is confirmed, start dexamethasone 16-24 mg daily immediately and taper over 2 weeks. 1
• Request urgent surgical evaluation for patients with good performance status, limited disease, and single compression site. 1

Long-Term ADT Monitoring

Continue ADT indefinitely to maintain castrate testosterone levels (<50 ng/dL) throughout all lines of mCRPC therapy. 1, 5

• Monitor for ADT-related complications including osteoporosis (bone densitometry), metabolic syndrome, and cardiovascular risk factors. 1, 3
• Verify serum testosterone remains <50 ng/dL; optimize ADT delivery or switch LHRH agents if inadequately suppressed. 5

Special Considerations and Common Pitfalls

Avoid these critical errors:

• Never discontinue ADT when starting novel hormone therapies, chemotherapy, or other systemic agents—all approved therapies for mCRPC were studied with concurrent ADT as backbone. 5
• Do not use radium-223 without concurrent bone-targeted therapy due to increased fracture risk demonstrated in ERA-223 trial. 1
• Do not sequence abiraterone after enzalutamide or vice versa as first choice post-progression—cross-resistance limits benefit; prefer chemotherapy or radium-223 instead. 1
• Do not start zoledronic acid or denosumab in castration-sensitive prostate cancer for SRE prevention—wait until development of mCRPC. 1

Neuroendocrine Differentiation

Consider small cell/neuroendocrine transformation in patients with:

• Low PSA despite large metastatic burden
• Visceral disease predominance
• Initial Grade Group 5 disease
• Lack of response to ADT

Biopsy accessible metastatic lesions to identify neuroendocrine histology; treat with platinum-based chemotherapy (cisplatin/etoposide or carboplatin/etoposide) rather than standard mCRPC therapies. 1

Treatment Algorithm Summary

1. Confirm castrate testosterone <50 ng/dL and continue ADT indefinitely 5
2. Initiate bone-targeted therapy: Denosumab 120 mg SC every 4 weeks (preferred) or zoledronic acid 4 mg IV every 3-4 weeks 1
3. Select systemic therapy based on symptoms and prior treatments:
   • Asymptomatic/mildly symptomatic, chemotherapy-naïve: Abiraterone or enzalutamide 1
   • Symptomatic bone-predominant without visceral disease: Radium-223 (with mandatory bone-targeted therapy) 1
   • Symptomatic or post-novel hormone therapy: Docetaxel 1, 3
   • Post-docetaxel progression: Cabazitaxel, or abiraterone/enzalutamide if not previously used 1, 4
4. Add single-fraction radiation (8 Gy) for painful bone lesions as needed 1, 3
5. Monitor for spinal cord compression with MRI surveillance and urgent evaluation for neurological symptoms 1, 3