Does Xaluritamig shrink bone metastases in metastatic castration-resistant prostate cancer (mCRPC)?

Xaluritamig Does Not Shrink Bone Metastases

Xaluritamig is not a bone-directed therapy and does not directly shrink bone metastases in metastatic castration-resistant prostate cancer (mCRPC). The drug is a T-cell engager immunotherapy that targets STEAP1-expressing cancer cells and demonstrated encouraging PSA and soft tissue responses (49% PSA50 reduction, 24% objective response rate by RECIST criteria), but RECIST criteria specifically measure soft tissue disease, not bone lesions 1.

Mechanism and Target of Xaluritamig

• Xaluritamig is a STEAP1 × CD3 bispecific antibody designed to facilitate T-cell-mediated lysis of STEAP1-expressing prostate cancer cells 1
• The drug works systemically through immune engagement rather than through bone-specific mechanisms like radiopharmaceuticals or bone-targeting agents 1
• At target doses ≥0.75 mg, the drug achieved 59% PSA50 responses and 41% objective response rates, but these measurements reflect systemic disease control and soft tissue responses, not bone metastasis shrinkage 1

Established Bone-Directed Therapies for mCRPC

For actual bone metastasis management in mCRPC, the evidence-based options are:

Radiopharmaceuticals for Bone Disease

• Radium-223 is the only bone-directed therapy proven to improve overall survival (3.6-month improvement) and delay symptomatic skeletal events (5.8-month delay) in patients with symptomatic bone-predominant mCRPC without visceral metastases 2
• Radium-223 delivers high-energy alpha particles to bone surfaces and osteoblastic stroma within metastases, providing direct anti-tumor effects on bone lesions 2
• Older beta-emitting agents (Strontium-89, Samarium-153) provide pain palliation but lack survival benefit and carry higher myelosuppression risk 2

Bone-Protective Agents (Not Tumor-Shrinking)

• Denosumab (120 mg subcutaneously every 4 weeks) or zoledronic acid (4 mg intravenously every 3-4 weeks) prevent skeletal-related events but do not shrink bone metastases 2
• These agents delay time to first skeletal-related event (pathologic fracture, spinal cord compression, radiation/surgery to bone) but have no impact on overall survival 2

External Beam Radiation for Palliation

• Single 8 Gy fraction provides equivalent pain relief to multi-fraction schedules for painful bone metastases 2
• Radiation provides local control and pain relief but does not systemically address multiple bone lesions 2

Critical Distinction: Systemic vs. Bone-Specific Activity

The key clinical caveat is that systemic therapies like xaluritamig, abiraterone, and enzalutamide may control the underlying cancer biology and potentially stabilize bone disease progression, but they do not directly shrink established bone metastases. 2, 1

• Bone metastases in prostate cancer are predominantly osteoblastic (bone-forming), making radiographic assessment of "shrinkage" problematic—successful treatment often causes increased sclerosis on CT, which can be misinterpreted as progression 2
• PSA responses and soft tissue responses do not reliably correlate with bone metastasis regression 2

Clinical Application for Xaluritamig

If considering xaluritamig for a patient with mCRPC and bone metastases:

• Use it for systemic disease control in heavily pretreated patients (the trial enrolled primarily taxane-pretreated patients) 1
• Combine with bone-protective agents (denosumab or zoledronic acid) to prevent skeletal-related events 2
• Add radium-223 if the patient has symptomatic bone-predominant disease without visceral metastases for actual bone-directed therapy with survival benefit 2
• Reserve external beam radiation for focal painful lesions requiring rapid palliation 2

The most common treatment-related adverse events with xaluritamig are cytokine release syndrome (72%, primarily cycle 1), fatigue (45%), and myalgia (34%), which require step-dosing and premedication strategies. 1