Can Pluvicto (Lutetium-177 vipivotide tetraxetan) eliminate bone metastasis in patients with metastatic castration-resistant prostate cancer?

Can Pluvicto Eliminate Bone Metastases in Metastatic Castration-Resistant Prostate Cancer?

Pluvicto (lutetium-177 vipivotide tetraxetan) does not eliminate bone metastases but significantly extends survival and delays disease progression in heavily pre-treated mCRPC patients with PSMA-positive disease. The drug delivers targeted radiation to cancer cells expressing PSMA, providing disease control rather than complete eradication of bone lesions 1, 2.

Understanding What Pluvicto Actually Does

Pluvicto is a radiopharmaceutical that binds to prostate-specific membrane antigen (PSMA) on cancer cells and delivers beta-particle radiation directly to these cells and their surrounding microenvironment 1, 2. This mechanism provides:

• Survival benefit: Median overall survival improved from 11.3 months to 15.3 months (hazard ratio 0.62) in the pivotal VISION trial 2
• Disease control: Median imaging-based progression-free survival extended from 3.4 months to 8.7 months (hazard ratio 0.40) 2
• Symptomatic improvement: Delayed time to symptomatic skeletal events 2

However, this represents disease control and slowing of progression, not elimination of existing bone metastases 3, 2.

Why Bone Metastases Cannot Be "Eliminated"

The nature of prostate cancer bone metastases makes radiographic assessment of "elimination" problematic:

• Osteoblastic biology: Prostate cancer bone metastases are predominantly bone-forming (osteoblastic), not bone-destroying 3
• Paradoxical imaging: Successful treatment often causes increased sclerosis on CT scans, which can be misinterpreted as progression rather than response 3
• Lack of shrinkage: Bone-protective agents like denosumab and zoledronic acid prevent skeletal-related events but do not shrink bone metastases 4, 3

Pluvicto's Role in the Treatment Algorithm

Pluvicto received FDA approval for patients with PSMA-positive mCRPC who have received:

1. At least one androgen receptor pathway inhibitor (abiraterone or enzalutamide) AND
2. One or two prior taxane-based chemotherapy regimens (typically docetaxel) 1, 5

Dosing: 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity 1, 6.

Comparison to Other Bone-Directed Therapies

Understanding Pluvicto's role requires distinguishing it from other bone-targeted treatments:

Radium-223 (The Only Other Survival-Improving Bone Therapy)

• Survival benefit: 3.6-month improvement in overall survival 3
• Mechanism: Delivers alpha particles to bone surfaces within metastases 3
• Indication: Symptomatic bone-predominant mCRPC without visceral metastases 3
• Key difference: Radium-223 targets bone microenvironment; Pluvicto targets PSMA-expressing cancer cells anywhere in the body 3, 2

Bone-Protective Agents (No Survival Benefit)

• Denosumab and zoledronic acid: Prevent skeletal-related events but do not shrink metastases or improve survival 4, 3
• Not recommended in castration-naïve disease: These agents should not be used until mCRPC develops 4

Older Radiopharmaceuticals (Pain Palliation Only)

• Strontium-89 and Samarium-153: Provide pain relief but lack survival benefit and carry higher myelosuppression risk 3, 7

Clinical Outcomes and Realistic Expectations

The VISION trial (831 patients) demonstrated:

• Objective response rate: Significantly higher with Pluvicto versus standard care alone 2
• Disease control: Achieved in majority of patients 2
• Quality of life: Not adversely affected despite higher grade 3+ adverse events (52.7% vs 38.0%) 2

Most common adverse effects (≥20%): Fatigue, dry mouth, nausea, anemia, decreased appetite, constipation 1, 2.

Laboratory abnormalities (≥30%): Decreased lymphocytes, hemoglobin, leukocytes, platelets, calcium, and sodium 1.

Critical Pitfalls to Avoid

1. Setting unrealistic expectations: Patients and families should understand Pluvicto provides disease control and survival extension, not cure or elimination of bone metastases 3, 2

2. Misinterpreting imaging: Increased bone sclerosis on CT after treatment may represent response, not progression, due to the osteoblastic nature of prostate cancer bone metastases 3

3. Confusing bone-protective agents with anti-tumor therapy: Denosumab and zoledronic acid prevent fractures and skeletal events but do not treat the cancer itself 4, 3

4. Using in wrong patient population: Pluvicto requires PSMA-positive disease on 68Ga-PSMA-11 PET/CT imaging and prior treatment with androgen receptor inhibitors and taxane chemotherapy 1, 2

5. Inadequate radiation safety protocols: Must be administered only by trained personnel in designated clinical settings with existing radiation safety protocols 6

6. Patient contact precautions: Patients must limit close contact and use bathroom precautions in days following treatment 6

The Bottom Line for Clinical Practice

Pluvicto represents a significant advance in mCRPC treatment, extending survival by approximately 4 months in heavily pre-treated patients 2. However, it does not eliminate bone metastases. The goal is disease control, symptom management, and prolongation of life. For patients seeking complete elimination of bone disease, this remains an unmet need in metastatic prostate cancer, and enrollment in clinical trials evaluating earlier use or combination strategies should be considered 6.